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Tag: Cell Biology

  • Study Shows Importance of Individual Molecules in Cells Under Mechanical Stress

    Study Shows Importance of Individual Molecules in Cells Under Mechanical Stress

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    Newswise — The cells in our body are continuously exposed to mechanical forces that are either externally applied or generated by the cells themselves. Being able to respond to such mechanical stimuli is an indispensable prerequisite for a large number of biological processes. However, how cells manage to process mechanical stimuli is poorly understood because techniques to study the very fine mechanical signals in cells are lacking. Researchers at the University of Münster (Germany) have now developed a method for altering the mechanics of individual molecules and thereby investigating their function within the cells. The findings have been published in the journal Science Advances.

    The team, headed by cell biologist Prof Carsten Grashoff, developed a method in which proteins can be altered with the help of a light-sensitive molecule and mechanically controlled by short light pulses. In this way, the scientists succeeded in breaking individual proteins with high temporal and spatial control enabling them to investigate their mechanical significance in the cells. Their first experiments demonstrated the function of two molecules that are not only important for the adhesion of cells but that are suspected of playing a central role in a number of diseases. The talin protein is essential for the carrying of mechanical forces during adhesion of cells in connective tissue – a process which is highly important in, for example, cell migration. In contrast, the desmoplakin protein is important for resisting mechanical stress in the cell-cell junctions that occur in epithelial tissues such as skin. “Together, these results provide evidence about how the mechanical properties of certain cell structures can be controlled by individual proteins,” says Carsten Grashoff.

    As the developed technique is genetically encoded and can, therefore, be inserted at any point into the genome, the researchers hope it will have broad applicability in the investigation of the mechanobiological properties of many other proteins in living cells, model organisms and disease models.

    Background details: Mechanical stimuli, like many other signals, are ultimately processed in cells at the level of individual proteins. Although researchers have, over the past few years, identified a range of molecules that are directly exposed to mechanical forces in cells, it has often remained unclear how important the mechanical contributions of individual proteins are in these often very complex cell-biological processes. The experiments carried out by Carsten Grashoff’s team succeeded by utilizing a light-sensitive connection that, despite being able to withstand a high degree of mechanical forces, breaks down when exposed to light radiation. Comparable light-sensitive proteins are found in plants, where they regulate the plant’s orientation to light. By inserting these predetermined breaking points into specific genes (talin, desmoplakin) using molecular biology techniques, the team produced cells of connective tissue and skin that could be controlled with a laser beam at the level of individual proteins. Modulation and analysis of the living cells, derived from mouse cell culture models, were achieved with fluorescence microscopy methods.

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    University of Munster

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  • 2023 Warren Alpert Foundation Prize Honors Pioneer in Computational Biology

    2023 Warren Alpert Foundation Prize Honors Pioneer in Computational Biology

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    Newswise — The 2023 Warren Alpert Foundation Prize has been awarded to scientist David J. Lipman for his visionary work in the conception, design, and implementation of computational tools, databases, and infrastructure that transformed the way biological information is analyzed and accessed freely and rapidly around the world.

    The $500,000 award is bestowed by The Warren Alpert Foundation in recognition of work that has improved the understanding, prevention, treatment, or cure of human disease. The prize is administered by Harvard Medical School. 

    Lipman will be honored at a scientific symposium on Oct. 11, 2023, hosted by HMS. For further information, visit The Warren Alpert Foundation Prize symposium website.

    Lipman, who is currently a senior science adviser for bioinformatics and genomics for the Food and Drug Administration, is receiving the award for work he did in the 1980s and 1990s prior to and after becoming the founding director of the National Center for Biotechnology Information (NCBI), a position he held until 2017.

    Lipman led the development of a powerful computational program called BLAST for the analysis and comparison of newly identified DNA and protein sequences against all known DNA and protein sequences. The tool transformed researchers’ ability to access and interpret DNA, RNA, and protein sequence data and propelled the fields of computational biology and molecular biology. While at the NCBI, Lipman also conceptualized and then oversaw the design and implementation of PubMed, the web-based database for biomedical literature used daily by millions of scientists, physicians, students, teachers, and the public. Today, NCBI houses multiple biotechnology databases and resources that, over the years, have reshaped biology, medicine, and other fields of science.

    “At a time when computation was deemed an exotic pursuit by most biomedical researchers, David was prescient because he understood the potential of computation to propel biomedical science forward,” said George Q. Daley, dean of HMS and chair of the Warren Alpert Foundation Prize scientific advisory board. “His vision, creativity, and rigor have transformed how scientists analyze and share data and, indeed, how we do science.”

    Lipman’s pioneering achievements not only democratized access to scientific information but also helped catalyze critical discoveries by enabling vital exchanges and collaborations among scientists in multiple fields of biomedicine and beyond.

    “The foundational work of David Lipman in the field of computational biology and the tools that he envisioned and created have an impact that is nearly impossible to measure on the fields of biology, medicine, and beyond,” said David M. Hirsch, director and chairman of the board of The Warren Alpert Foundation. “His contributions exemplify the mission and vision of the Warren Alpert Foundation.”

    Significance of the work

    Over the past 40 years, advances in DNA sequencing, computation, and the internet have transformed biomedical research, public health, and the practice of medicine. Lipman developed many of the most important computational tools and infrastructure for making discoveries with these technologies.  

    In the 1980s, as understanding of DNA and genes began to accelerate, elucidating the evolutionary relationships across genes and proteins within and between species became a major focus of Lipman’s scientific curiosity and research efforts. Such knowledge is critical in elucidating evolutionary relationships that provide essential clues about the function of genes and proteins.

    Early on, Lipman realized that the rapid emergence of new genetic sequencing data would require powerful and efficient computer programs to compare one DNA or protein sequence against all known sequences.

    In a series of papers published between 1983 and 1990, Lipman pioneered the design of multiple methods for comparative sequence analysis. This culminated in the development of an algorithm called BLAST, described in a now seminal 1990 paper. Today, BLAST and subsequent programs, gapped BLAST, and PSI-BLAST remain among the most widely used tools in biology and medicine and are deemed among the most significant achievements in the field of computational biology of the past 40 years.

    BLAST enabled understanding of the interplay between genes, biology, physiology, and the environment across organisms and has led to important discoveries in nearly all areas of biomedical research, from the molecular basis of cancer to identifying the source of a foodborne outbreak. 

    Furthermore, Lipman became one of the most ardent supporters of and key figures in the move toward open-access science. He was instrumental in the design of PubMed, the open-access scientific publication resource of the NCBI and the largest and most widely used resource for scientific research in the world.

    As director of NCBI, Lipman oversaw GenBank, the world’s largest DNA and protein sequence repository, an international collaboration among the United States, Japan, and Europe. Under his direction, NCBI brought GenBank into the era of genomics and the internet, vastly augmenting its capabilities.

    From the winner

    “Through the creation of computational tools and information systems, my goal and that of the wonderful collaborators I’ve had the honor to work with has been to enable biomedical researchers to make discoveries. The scientists involved in the nomination and selection process have a deep understanding of the field and have themselves made some of the most important biomedical discoveries. So, this honor holds a special significance to me.”

                -David J. Lipman

    The prize

    The Warren Alpert Foundation Prize recognizes the research of scientists throughout the world. Including the 2023 prize, the foundation has awarded more than $7.5 million to 79 individuals. Since the inception of the award in 1987, 12 honorees have gone on to receive Nobel prizes.

    The 2022 Warren Alpert Foundation Prize was awarded to Drew Weissman, Katalin Karikó, Uğur Şahin, Özlem Türeci, and Eric Huang for pioneering discoveries into the biology of mRNA, for its modification for medicinal use, and for the design of mRNA-based COVID-19 vaccines that set the stage for other mRNA vaccines and a variety of mRNA-based therapies.

    Other past recipients include:

    • Lynne Maquat and Joan Steitz for discoveries in the biology and function of RNA that reshaped the understanding of RNA’s various roles in healthy cell function and disease-causing dysfunction.
    • Daniel Drucker, Joel Habener, and Jens Juul Holst for elucidating the function of key intestinal hormones, their effects on metabolism, and the subsequent design of treatments for type 2 diabetes, obesity, and short bowel syndrome.
    • Edward Boyden, Karl Deisseroth, Peter Hegemann, and Gero Miesenböck for pioneering work in the field of optogenetics.
    • Francis Collins, Paul Negulescu, Bonnie Ramsey, Lap-Chee Tsui, and Michael Welsh for discoveries in cystic fibrosis.
    • James Allison, Lieping Chen, Gordon Freeman, Tasuku Honjo, and Arlene Sharpe for discoveries into cancer’s ability to evade immune surveillance, which led to the development of a class of cancer immunotherapies. Allison and Honjo shared the 2018 Nobel Prize in Physiology or Medicine.
    • Rodolphe Barrangou, Emmanuelle Charpentier, Jennifer Doudna, Philippe Horvath, and Virginijus Siksnys for CRISPR-related discoveries. Doudna and Charpentier shared the 2020 Nobel Prize in Chemistry.
    • Tu Youyou, who went on to receive the 2015 Nobel Prize in Physiology or Medicine with two others, and Ruth and Victor Nussenzweig for their pioneering discoveries in the chemistry and parasitology of malaria and the translation of that work into the development of drug therapies and an antimalarial vaccine.
    • Oleh Hornykiewicz, Roger Nicoll, and Solomon Snyder for research into neurotransmission and neurodegeneration.
    • Alain Charpentier and Robert Langer for innovations in bioengineering.
    • Harald zur Hausen and Lutz Gissmann for work on the human papillomavirus (HPV) and its role in cervical cancer. Zur Hausen and others were honored with the Nobel Prize in Physiology or Medicine in 2008.

    The Warren Alpert FoundationEach year the Warren Alpert Foundation receives between 30 and 50 nominations from scientific leaders worldwide. Prize recipients are selected by the foundation’s scientific advisory board, which is composed of distinguished biomedical scientists and chaired by the dean of Harvard Medical School. Warren Alpert (1920-2007), a native of Chelsea, Mass., established the prize in 1987 after reading about the development of a vaccine for hepatitis B. The inaugural recipient of the award was Kenneth Murray of the University of Edinburgh, who designed the hepatitis B vaccine. To award subsequent prizes, Alpert asked Daniel Tosteson (1925-2009), then dean of Harvard Medical School, to convene a panel of experts to identify scientists from around the world whose research had a direct impact on the treatment of disease. 

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    Harvard Medical School

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  • Mayo Clinic Expert Addresses Cancer Disparities During Black Family Cancer Awareness Week

    Mayo Clinic Expert Addresses Cancer Disparities During Black Family Cancer Awareness Week

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    Newswise — ROCHESTER, Minn. – Black people have the highest death rate and shortest survival rate of any racial or ethnic group for most cancers, according to the American Cancer Society. In Black men, prostate cancer death rates are more than double that of any other racial or ethnic group, and Black women are 40% more likely to die of breast cancer than white women.

    These disparities are driving many efforts to raise awareness about cancer prevention and care in Black communities, such as Black Family Cancer Awareness Week, which takes place June 15–21.

    Mayo Clinic expert Kim Barbel Johnson, D.O., says culture differences, personal behaviors, genetics and health literacy all contribute to a person’s access to cancer care, routine preventive screenings and, ultimately, their cancer risk.

    “It’s important for healthcare providers to continue to educate and provide resources to members of the Black community about cancer prevention and the importance of getting screened early and regularly, especially if there is a history of cancer in the family,” says Dr. Barbel Johnson, a primary care doctor and director of Community Clinical Trials at Mayo Clinic Comprehensive Cancer Center. “I encourage people to talk openly with members of their family to learn about the family’s health history and to stay in touch with their primary care provider who can provide support and resources about prevention, screenings and cancer care.”

    More diverse racial and ethnic participation in cancer research is also important to understand and improve outcomes for people in those groups, Dr. Barbel Johnson adds.  

    “In order to make advances in lowering the death rates for the Black community, we must reach out and encourage underrepresented populations to be part of the solution that will advance the science that brings them earlier cancer therapies,” says Dr. Barbel Johnson. “Cancer care is not one-size-fits-all, and having Black people participate in clinical trials may lead to better responsive medications, more effective medications and more effective screening tools.”

    If patients are educated about cancer, prevention, screening and care, they will feel empowered to become advocates for themselves and for others, she says.

    Dr. Barbel Johnson is available for interviews on health disparities and ways to improve access to care, how families can plan conversations about family health history, encouraging preventive screenings and ways to participate in cancer research.

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    About Mayo Clinic Comprehensive Cancer Center
    Designated as a comprehensive cancer center by the National Cancer Institute, Mayo Clinic Comprehensive Cancer Center is defining new boundaries in possibility, focusing on patient-centered care, developing novel treatments, training future generations of cancer experts, and bringing cancer research to communities. At Mayo Clinic Comprehensive Cancer Center, a culture of innovation and collaboration is driving research breakthroughs that are changing approaches to cancer prevention, screening, and treatment and improving the lives of cancer survivors.

    About Mayo Clinic
    Mayo Clinic     is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

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    Mayo Clinic

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  • DNA shape and packing manipulation: groundbreaking method

    DNA shape and packing manipulation: groundbreaking method

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    Newswise — A human cell harbors roughly 2 meters of DNA, encompassing the essential genetic information of an individual. If one were to unwind and stretch out all the DNA contained within a single person, it would span a staggering distance – enough to reach the sun and back 60 times over. In order to manage such an astounding volume of biological information, the cell compacts its DNA into tightly packed chromosomes.

    “Imagine DNA as a piece of paper upon which all our genetic information is written.” Says Minke A.D. Nijenhuis, co-corresponding author. “The paper is folded into a very tight structure in order to fit all of that information into a small cell nucleus. To read the information, however, parts of the paper have to be unfolded and then refolded. This spatial organization of our genetic code is a central mechanism of life. We therefore wanted to create a methodology that allows researchers to engineer and study the compaction of double-stranded DNA.”

    Triple helical structure provides protection and compactness

    Natural DNA is often double-stranded: one strand to encode the genes and one backup strand, intertwined in a double helix. The double helix is stabilized by Watson-Crick interactions, which allow the two strands to recognize and pair with one another. Yet there exists another, lesser-known class of interactions between DNA. These so-called normal or reverse Hoogsteen interactions allow a third strand to join in, forming a beautiful triple helix (Figure 2).

    In a recent paper, published in Advanced Materials, researchers from the Gothelf lab debut a general method to organize double-stranded DNA, based on Hoogsteen interactions. The study unambiguously demonstrates that triplex-forming strands are capable of sharply bending or “folding” double-stranded DNA to create compacted structures. The appearance of these structures range from hollow two-dimensional shapes to dense 3D constructs and everything in-between, including a structure resembling a potted flower. Gothelf and co-workers have named their method triplex origami (Figure 3).

    With triplex origami, scientists can achieve a level of artificial control over the shape of double-stranded DNA that was previously unimaginable, thereby opening new avenues of exploration. It has recently been suggested that triplex formation plays a role in the natural compaction of genetic DNA and the current study may offer insight into this fundamental biological process.

    Potential in gene therapy and beyond

    The work also demonstrates that the Hoogsteen-mediated triplex formation shields the DNA against enzymatic degradation. Hence, the ability to compact and protect DNA with the triplex origami method may have large implications for gene therapy, wherein diseased cells are repaired by encoding a function that they are missing into a deliverable piece of double-stranded DNA.

    This biological marvel of DNA sequence and structure has also been applied in nanoscale materials engineering, yielding applications in therapeutics, diagnostics, and many other areas. “For the past four decades, DNA nanotechnology has almost exclusively relied on Watson-Crick base interactions to pair up single DNA strands and organize them into custom nanostructures.” Says Professor Kurt V. Gothelf. “We now know that Hoogsteen interactions have the same potential to organize double-stranded DNA, which presents a significant conceptual expansion for the field.”

    Gothelf and co-workers demonstrated that Hoogsteen-mediated folding is compatible with state-of-the-art Watson-Crick-based methods. Due to comparative rigidity of double-stranded DNA, however, triplex origami structures require fewer starting materials. This allows larger structures to be formed at significantly lower cost.

    The new method has the limitation that triplex formation typically requires long stretches of purine bases within the double-stranded DNA and the researchers have therefore used artificial DNA sequences, instead of natural genetic DNA. However, in the future they will work towards overcoming this limitation.

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    Aarhus University

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  • New Research Shows HIV Can Lie Dormant in the Brain

    New Research Shows HIV Can Lie Dormant in the Brain

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    Newswise — CHAPEL HILL, N.C. – As a part of its life cycle, the human immunodeficiency virus-1 (HIV) inserts a copy of its DNA into human immune cells. Some of these newly infected immune cells can then transition into a dormant, latent state for a long period of time, which is referred to as HIV latency.

    Although current therapies, such current antiretroviral therapy (ART), can successfully block the virus from replicating further, it cannot eradicate latent HIV. If treatment is ever discontinued, the virus can rebound from latency and reignite the progression of HIV infection to AIDS.

    Scientists from the HIV Cure Center at the UNC School of Medicine, University of California San Diego, Emory University, and University of Pennsylvania have been searching for where exactly these latent cells are hiding in the body. New research published in the Journal of Clinical Investigations confirms that microglial cells – which are specialized immune cells with a decade-long lifespan in the brain – can serve as a stable viral reservoir for latent HIV.

    “We now know that microglial cells serve as a persistent brain reservoir,” said first author Yuyang Tang, PhD, assistant professor of medicine in the Division of Infectious Diseases and member of the UNC HIV Cure Center. “This had been suspected in the past, but proof in humans was lacking. Our method for isolating viable brain cells provides a new framework for future studies on reservoirs of the central nervous system, and, ultimately, efforts towards the eradication of HIV.”

    Latent HIV

    HIV is a tricky and unique virus to study. During infection, the virus specifically targets the key coordinators of the immune response, which are called CD4+ lymphocytes. Over time, the virus kills enough CD4+ cells to cause immunodeficiency. .

    Past research has shown that latent HIV can hide within a few of the surviving CD4+ T cells throughout the body and the bloodstream. However, other viral reservoirs have been suspected to hide within the central nervous system (CNS) in people with HIV receiving effective ART.

    Unlike peripheral blood cells, it is extremely difficult to access and analyze brain tissues for the study of HIV reservoirs. Since these types of cells cannot be safely sampled in people taking ART,he potential viral reservoir in the brain has remained an enigma for many years.

    Extracting Pure Brain Tissue

    The team first studied the brains of macaques with the simian immunodeficiency virus (SIV), a virus that is closely related to HIV, from the Yerkes National Primate Research Center at Emory University to get a better understanding of how to extract and purify viable cells from primate brain tissue.

    Researchers used physical separation techniques and antibodies to selectively remove cells that were expressing microglial surface markers. Then, they isolated and separated the highly pure brain myeloid cells from the CD4+ cells that were passing through the brain tissue.

    Using these techniques, researchers then obtained samples that were donated by HIV+ people who were enrolled in “The Last Gift” Study at the University of California San Diego (UCSD). As a part of this unique and important effort, altruistic HIV+ people, who aretaking ART but suffering from other terminal illnesses, will their bodies to further the HIV research project.

    “The samples are from people living with HIV, who are on therapy but facing a fatal disease of some kind,” said the co-author David Margolis, MD, the Sarah Kenan Distinguished Professor of Medicine, Microbiology & Immunology, and Epidemiology. “They were willing to not just donate their bodies to science, but also participate in the research program in the months leading up to their death. It’s an extraordinary program that made this critical research possible.”

    Now that the researchers know that latent HIV can take refuge in microglial cells in the brain, they are now considering plans to target this type of reservoir. Since latent HIV in the brain is radically different from the virus in the periphery, researchers believe that it has adapted special characteristics to replicate in the brain.

    “HIV is very smart,” said senior author Guochun Jiang, PhD, assistant professor in the UNC Department of Biochemistry and Biophysics and member of the UNC HIV Cure Center. “Over time, it has evolved to have epigenetic control of its expression, silencing the virus to hide in the brain from immune clearance. We are starting to unravel the unique mechanism that allows latency of HIV in brain microglia”.”

    NF-κB signaling is one of the critical signaling pathways that controls HIV expression elsewhere in the body. When NF-κB signaling is ”turned off”, HIV enters latency in the peripheral blood. However, it seems that latent HIV in the brain is not impacted by the activation of NF-κB signaling. Researchers are unsure why that is, but once an answer is found, they will be one step closer to knowing how to selectively target and eradicate the virus in the brain or peripheral blood.In addition to understanding the inner workings of the brain reservoir, the researchers are also trying to determine the true size of the latent HIV brain reservoir. 

    “It is very hard to know how big the reservoir is,” said Margolis, who is also the director of the UNC HIV Cure Center. “The problem with trying to eradicate HIV is like trying to eradicate cancer. You want to be able to get it all, so it won’t come back.”

    About UNC School of Medicine The UNC School of Medicine (SOM) is the state’s largest medical school, graduating more than 180 new physicians each year. It is consistently ranked among the top medical schools in the US, including 7th overall for primary care by US News & World Report, and 7th for research among public universities. More than half of the school’s 1,700 faculty members served as principal investigators on active research awards in 2021. Two UNC SOM faculty members have earned Nobel Prize awards.

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    University of North Carolina School of Medicine

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  • Target found for prostate cancer resistant to hormone therapy

    Target found for prostate cancer resistant to hormone therapy

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    Newswise — Prostate cancer is the most-commonly diagnosed malignancy and the second leading cause of cancer death among men in the United States. In its ever-indelicate world, the stubborn disease can continue to grow even when the amount of testosterone in the body is reduced to very low levels, thus earning the clumsy name: castrate-resistant prostate cancer (CRPC). It poses a major clinical challenge as a protein called the androgen receptor (AR) remains behind as a critical player in cancer, changing its behavior in CRPCs. 

    Androgen-deprivation therapy, which is a treatment that reduces the levels of male hormones, is the first-line treatment for locally advanced or metastatic prostate cancer. Despite initial responses to the therapy, nearly all patients eventually develop CRPC within a few years. It is now well recognized that CRPC continues to be dependent on AR signaling. 

    “Understanding the triggers that cause changes in AR’s activity is important for developing better treatments for CRPCs,” said Ping Yi, assistant professor of biology and biochemistry, who is leading a team investigating CRPC. Yi’s research is published in PNAS. Her research team includes Ramesh Singh, Lance Lumahan and Hong Shen, Department of Molecular and Cellular Biology, Baylor College of Medicine; and Steven Nguyen, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston. 

    “We found a specific chemical modification that occurs on the AR protein in certain conditions where the levels of male hormones are reduced to castration conditions. This modification involves another protein called TRAF4, which is frequently overexpressed in advanced prostate cancers. We demonstrated that overexpression of TRAF4 leads to the conversion of androgen-sensitive prostate cancer cells into castration-resistant cells, both in lab experiments and in live samples,” said Yi. “We also found that the TRAF4 protein level is higher in androgen-insensitive lymph node carcinoma cells of the prostate.” 

    The findings also suggest that TRAF4 is associated with promoting the spread of cancer to other parts of the body. For this research Yi examined cells of patients with metastatic cancer who had previously undergone androgen-deprivation therapy. The researchers also observed that the TRAF4 protein is higher in cancer cells that are no longer responsive to androgens compared to cells that still respond to androgens. 

    The researchers believe that their findings provide an important basis for identifying a group of CRPC patients who might respond well to a treatment potentially targeting the specific molecular changes caused by the AR modification, providing a possible treatment option for this group of patients. 

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    University of Houston

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  • Study reveals how treatment-resistant prostate cancer provides its own hormonal fuel

    Study reveals how treatment-resistant prostate cancer provides its own hormonal fuel

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    BYLINE: Julia Evangelou Strait

    Newswise — A new study in mice, led by researchers at Washington University School of Medicine in St. Louis, explains how prostate cancer senses a drop in testosterone levels due to common anti-hormone therapy and then begins making cholesterol — a necessary precursor to testosterone — to generate its own testosterone to fuel tumor growth. The study also points to a possible drug combination that may stop the cancer from feeding its own growth.

    Healthy prostate cells do not produce testosterone, so the research provides long-sought answers to questions about how prostate cancer cells adapt to testosterone-deprivation therapy, a common therapeutic option, by developing an ability to supply their own hormonal fuel. Further, the research reveals that treating these aggressive prostate tumors with inhibitors that block aspects of the hormonal fuel supply chain slows tumor growth in mice. These findings suggest a novel treatment strategy for prostate cancer that has become resistant to the common anti-testosterone therapy abiraterone.

    The study appears June 9 in the journal Nature Communications.

    The study also may help explain why Black men are at higher risk of developing prostate cancer and tend to develop more aggressive forms of the cancer than white men of European ancestry.

    “We’ve known for a long time that androgens, or male hormones such as testosterone, fuel prostate tumors — and we have drugs to treat prostate cancer that block the body’s ability to make testosterone,” said senior author Nupam Mahajan, PhD, a professor of surgery in the Division of Urologic Surgery. “But after about a year, these drugs stop working, and the androgen levels rise again. Where is this androgen coming from? Turns out, prostate cancer cells have learned a new trick; they start producing more cholesterol, which they divert to generate their own androgen. Our study shows how to block this, revealing a possible drug combination that could stop prostate cancer from fueling its own growth.”

    Mahajan is also a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

    The study demonstrated how the prostate cancer cells first detect that androgen levels have dropped. The researchers found that a key protein called SREBF1, when bound to the androgen receptor, acts as an androgen sensor. When androgen levels are low, this protein enters the cancer cell nucleus, recruits an enzyme, GCN5, to modify proteins called histones through a process called acetylation. This epigenetic modification activates many genes important for manufacturing cholesterol and lipids. According to Mahajan, these two molecular events allow the cells to make enormous amounts of cholesterol, a necessary precursor for testosterone.

    “The cancer cells essentially load up the tumor with cholesterol and use that cholesterol to churn out more testosterone,” Mahajan said. “That’s the trick. They overload the prostate with cholesterol, and the normal systems for making androgen from cholesterol just work as they typically would, making drugs like abiraterone ineffective.”

    Mahajan and his colleagues experimented with two inhibitors that block the molecular events that they found to be responsible for the massive cholesterol manufacturing. They used these inhibitors to treat mice that had prostate tumors that had been sampled from human patients.

    One drug is afatinib, an EGFR inhibitor approved by the Food and Drug Administration to treat certain types of lung cancer. The second drug is a GCN5 inhibitor. GCN5 inhibitors have not yet made it into clinical trials, but Mahajan said there is great interest in developing this class of drugs, which could have an effect on gene regulation, cell growth and inflammation. Mice treated with a combination of these two inhibitors showed large reductions in tumor volume compared with mice treated with placebo or the anti-testosterone drug abiraterone alone.

    The study also suggests that the cholesterol abundance in aggressive prostate cancer may shed light on racial disparities seen in this tumor type. The researchers found evidence that the lipid profile of prostate cancer in African American men resembles the lipid profile of treatment-resistant prostate cancer identified in this study. In other words, for reasons that remain unclear, African American men with prostate cancer appear to be more prone to having an abundance of cholesterol in their tumors than white men with the same tumor type.

    “This is preliminary data, so we need to verify it in larger studies,” Mahajan said. “But our study suggests that this cholesterol profile may play an important role in African American patients with prostate cancer. African American men are at higher risk of prostate cancer, are diagnosed at earlier ages, and now we see that the kinds of cholesterol molecules that are generated in their cancers are similar to what we see in this overactive cholesterol manufacturing pathway. Their cancers are more likely to already be making these lipids, even before beginning anti-testosterone treatment.”

    “We are hopeful this study will provide a solid rationale for undertaking a clinical trial of these two inhibitors combined — to block this cholesterol pathway — in patients with treatment-resistant prostate cancer,” Mahajan added.

     

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    Nguyen T, Sridaran D, Chouhan S, Weimholt C, Wilson A, Luo J, Li T, Koomen J, Fang B, Putluri N, Sreekumar A, Feng FY, Mahajan K, Mahajan NP. Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer. Nature Communications. June 9, 2023.

    This work was supported by the National Institutes of Health (NIH), grant numbers 1R01CA208258, 5R01CA227025, 1R01CA273054, NCATS UL1 TR000448, NIGMS P41 GM103422, NCI P30 CA091842, P30 CA076292 and P30 CA125123; the Prostate Cancer Foundation, grant number 17CHAL06; a Department of Defense award, number PC200201; the Cancer Prevention and Research Institute of Texas, grant number RP210227; and the Dan L. Duncan Cancer Center.

    About Washington University School of Medicine

    WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

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    Washington University in St. Louis

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  • COVID-19 Linked to Brain Cell Fusion

    COVID-19 Linked to Brain Cell Fusion

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    Newswise — Scientists at The University of Queensland have unveiled that viruses like SARS-CoV-2 can induce fusion among brain cells, triggering dysfunctions that result in persistent neurological symptoms.

    Professor Massimo Hilliard and Dr Ramon Martinez-Marmol, researchers at the Queensland Brain Institute, have delved into the mechanisms by which viruses disrupt the functioning of the nervous system.

    SARS-CoV-2, the culprit behind COVID-19, has been identified in the brains of individuals experiencing persistent symptoms, commonly referred to as ‘long COVID,’several months after their initial infection.

    “COVID-19 induces a novel cell fusion process in neurons, a phenomenon we have uncovered,” Professor Hilliard remarked.

    “Following neuronal infection with SARS-CoV-2, the neuronal cells exhibit the presence of spike S protein, and remarkably, upon fusion, these neurons do not undergo cell death,” explained the researcher.

    “They either start firing synchronously, or they stop functioning altogether.”

    Drawing an analogy, Professor Hilliard compared the function of neurons to the wiring that connects switches to the lights in a kitchen and a bathroom.

    “Once fusion occurs, each switch has the potential to either activate both the kitchen and bathroom lights simultaneously or leave them both unlit,” he elaborated.

    “It’s bad news for the two independent circuits.”

    The discovery offers a potential explanation for persistent neurological effects after a viral infection.

    “In the prevailing understanding of viral entry into the brain, there are typically two outcomes: either cell death or inflammation,” noted Dr. Martinez-Marmol.

    “But we’ve shown a third possible outcome, which is neuronal fusion.”

    Dr. Martinez-Marmol highlighted that various viruses not only induce cell fusion in other tissues but also infect the nervous system, potentially leading to similar issues in that particular context.

    “These viruses include HIV, rabies, Japanese encephalitis, measles, herpes simplex virus and Zika virus,” he said.

    “Our research reveals a new mechanism for the neurological events that happen during a viral infection.

    “This is potentially a major cause of neurological diseases and clinical symptoms that is still unexplored.”

    The researchers gratefully acknowledge the collaborative contributions of Professor Lars Ittner and Associate Professor Yazi Ke from Macquarie University, Associate Professor Giuseppe Balistreri from the University of Helsinki, and Associate Professor Kirsty Short and Professor Frederic Meunier from The University of Queensland.

    The research was published in Sciences Advances.

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    University of Queensland

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  • A Potential Biomarker for Pediatric Acute Liver Failure

    A Potential Biomarker for Pediatric Acute Liver Failure

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    BYLINE: Katie Sweeney

    Newswise — A tiny population of T-cells could serve as a much-needed biomarker—and a potential therapeutic target—for pediatric acute liver failure, according to new research from Children’s Hospital Los Angeles.

    The study, led by surgeon-scientist Juliet Emamaullee, MD, PhD, found that T-cells expressing a molecule called programmed cell death protein 1 (PD-1) were present only in the biopsies of children who recovered from acute liver failure without needing a liver transplant.

    The findings were presented in a plenary session at the 2023 International Congress of the International Liver Transplantation Society, held May 3-6 in Rotterdam, Netherlands. First author Brittany Rocque, MD, MSc, a general surgery resident in Dr. Emamaullee’s lab, presented the research.

    The team will also present the study findings in a plenary session on June 5 at the American Transplant Congress in San Diego.

    “It’s an exciting discovery because this is something you could look for in a liver biopsy that could potentially give you valuable information about which children are more likely to need a liver transplant,” explains Dr. Emamaullee, a surgeon and Research Director in the Division of Abdominal Organ Transplantation at CHLA. “But it also opens up a possible treatment pathway.”

    Pinpointing single cells

    Pediatric acute liver failure is a rapidly progressing and potentially life-threatening illness that affects otherwise healthy children. The condition comes on with few warning signs before a child presents in the emergency room.

    Approximately 10% to 15% of patients will end up undergoing a liver transplant. However, many children recover without the need for a transplant and the resulting lifetime of immunosuppression medications. But without reliable predictors of a patient’s trajectory, it can be challenging for physicians to decide when they should move forward with a transplant, and when they should wait.

    In search of biomarkers that could help guide these decisions, Dr. Emamaullee and her team conducted a retrospective study examining liver biopsies from 27 children with acute liver failure. Eleven of those children received a liver transplant; 16 of them recovered without a transplant.

    The researchers used a technology called imaging mass cytometry to uncover individual immune cells present in each biopsy. The technology produces images that allow researchers to examine up to 40 different proteins in a single cell, all at the same time, from a small section of tissue.

    Although imaging mass cytometry is more common in cancer research, the Children’s Hospital Los Angeles team is the only group in the world using it to investigate immune cells in this way. The team has also developed advanced computational biology techniques that turn the images from the technology into a single-cell dataset.

    After identifying more than 83,000 immune cells from the biopsies, the investigators discovered the small population of T-cells expressing PD-1. The cells were found only in patients who had recovered without a transplant.

    “These cells are relatively rare; they’re less than 1% of the cells that we see in the biopsy,” Dr. Emamaullee says. “It’s only because of this technology and this advanced analysis that we were able to find them. Using older techniques, you would never know they were there.”

    Dysregulated inflammation

    It’s already well understood that PD-1 acts like a brake on the immune system, preventing T-cells from attacking the body’s normal tissue. In cancer therapy, a class of immunotherapy drugs called checkpoint inhibitors specifically blocks PD-1 expression on T-cells.

    The idea in cancer is to “take the brakes off” and give T-cells free rein to fight a tumor. But in pediatric acute liver failure, Dr. Emamaullee says, the opposite effect may be needed. Instead of releasing the PD-1 brake, you may need to apply it.

    “In acute liver failure, you have this dysregulated inflammation occurring,” she explains. “It appears that you may need T-cells expressing PD-1 to shut down this inflammation and let the liver recover. This also opens up a potential therapeutic target. If we could give a treatment that increases PD-1 expression, then maybe we could shut down this acute inflammation.”

    She adds that PD-1 may also play a key role in liver transplant rejection—another area her team is studying. “We think that these cells are likely important for mediating liver inflammation overall,” she notes. “That could have implications for many different kinds of inflammatory liver disorders.”

    The team’s next step is to study a larger sample of patients, with the goal of better understanding the role these particular T-cells play, as well as their spatial interactions with other cell types in the areas of inflammation. The researchers are also investigating the degree of liver regeneration that occurs during recovery from pediatric acute liver failure.

    Study co-authors were Johanna Ascher Bartlett, MD, of CHLA; Tricia Saputera of USC; Sarah Bangerth, Arianna Barbetta and Bryce Roper, of the Keck School of Medicine of USC; and Carly Weaver and Rohit Kohli, MBBS, MS, of CHLA. Pediatric Pathologist Shengmei Zhou, MD, also of CHLA, is a research collaborator with the team.

    Learn more about liver care at Children’s Hospital Los Angeles.

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    Children’s Hospital Los Angeles

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  • Promising Phase III Results Give Hope to People Living with Myelodysplastic Syndromes

    Promising Phase III Results Give Hope to People Living with Myelodysplastic Syndromes

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    Newswise — Amer Zeidan, MBBS, medical director of the hematology early therapeutics research program at Yale Cancer Center and associate professor of medicine (hematology) at Yale School of Medicine, will reveal new data at the American Society of Clinical Oncology (ASCO) annual meeting from a phase III study evaluating the efficacy of imetelstat in red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndrome (LR-MDS) patients. Myelodysplastic syndromes(MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The study results demonstrate significant and clinically meaningful efficacy, representing a potential breakthrough in the treatment of anemic LR-MDS.

    Imetelstat, a telomerase inhibitor, was evaluated in patients who were heavily RBC transfusion-dependent LR-MDS and who were refractory or ineligible for erythropoiesis-stimulating agents (ESAs), but did not receive lenalidomide or hypomethylating agents (other drugs used to treat MDS). The phase III study, known as IMerge, enrolled a total of 178 patients. The findings from the study provide critical evidence supporting imetelstat’s efficacy and safety profile. These results are expected to have a substantial impact on future treatment strategies for patients diagnosed with LR-MDS.

    Dr. Zeidan, first and presenting author of the research at ASCO, answered questions on the study and its significance for patients living with MDS:

    Q: What is the significance of this study?

    A: “This is a very important study. Imetelstat is a first-in-class agent. It’s a first-in-class telomerase inhibitor, and this is the first time we have a phase III study of a drug in this class. We already completed the phase II study that was single arm that looked at a similar population of patients with lower risk MDS (myelodysplastic syndromes) who are heavily transfusion dependent, and the transfusion independence rate with the drug was around 40%. Transfusions in MDS are associated with increased risk of complications, increased risk of death, not to mention healthcare utilization and costs. So, trying to reduce transfusions and ideally make patients transfusion independent is a very important goal of treatment in patients with lower risk MDS.

    So the excellent activity of imetelstat in the phase II part of the study was taken to a phase III trial and what we have found in this study is what we actually expected based on the phase II trial: the transfusion dependence rate was much better with imetelstat compared to placebo, it was around 40% for an eight-week duration of transfusion dependence, the primary endpoint of the study, compared to 15% with a placebo; and most importantly, it was also durable. The median duration of transfusion independence for those who responded was more than 50 weeks. So clearly, a very positive study, very consistent with the phase II data. I think this drug could become an important option for patients.”

    Q: What are the key findings from the data? What will you highlight at ASCO?

    A: “During the ASCO presentation, we’ll discuss in detail, the efficacy of the drug in terms of transfusion independence, hematologic improvement, durability of response, but also looking within subgroups for patients based on the genetic profile. We will also discuss early signs of disease modification that we are seeing through reduction of variable allele frequency of important mutations that contribute to the pathogenesis of MDS. We’ll also discuss the side effect profile and how the interruption of therapy has led to, I think, a manageable and reversible side-effect profile, mostly in the setting of liver enzyme abnormalities and cytopenias (a medical condition where there are a low number of red blood cells).”

    Q: Are there other treatment options for this niche group of patients affected by this cancer?

    A: “Yes, so myelodysplastic syndromes have been renamed neoplasms by the World Health Organization, the most recent classification to emphasize that it’s a cancer. Many people think of MDS as an anemia or a pre-leukemia or a syndrome, but they are actually cancers. However, they differ in their severity. Patients in general are grouped into two big groups, lower risk and higher risk. In lower risk patients, those patients can live for years, but they have a lot of complications related to the low blood counts. That could be anemia, thrombocytopenia, or neutropenia, or a combination of these, but the most common use cytopenia is anemia. Anemia often is associated with reduced quality of life. The patient often needs regular transfusions. It’s also associated with significant complications and high risk of death, as well as issues related to needing to go to the clinic frequently, healthcare utilization costs. Correction of anemia is very important. Historically, the only treatment we had was erythropoiesis stimulating agents for patients with lower risk MDS. In recent years, other drugs have been approved like lenalidomide, as well as hypomethylating agents and luspatercept. However, the response to these drugs is limited, and at some point, the patient will progress and will need additional treatment. I think imetelstat potentially could fill a very important gap there because those patients are generally not going to be cured without a bone marrow transplant, which is not something that’s commonly done in MDS patients where the average age is in the early 70s. The goal is to try to improve quality of life in those lower risk MDS patients and make them transfusion independent as much as possible and that’s generally achieved by sequential therapy. So you go from one agent to the next, while trying to maintain quality of life keeping the patient out of the hospital and minimizing complications of the treatment itself.”

    Q: What is next in terms of research. What would you like done in future studies?

    A: “This is a very important question. I think the next step is going to be focusing more on how to increase the overall durability of response as well as increased the rate of response. And I think that’s going to be done by combining drugs. We have several active drugs now. So, figuring out how to combine them, and probably trying to treat patients earlier in their disease course will be important, so they don’t even get to the point of becoming transfusion dependent. Several of those studies I think are going to happen over the next few years. And of course, there are other drugs that are being studied in phase I and phase II trials. Some of those hopefully will also lead to benefit to patients so that if we cannot cure the disease, we can for most patients at least improve their quality of life, make transfusions as least as possible, and also make sure they are out of the hospital and having a good quality of life.”

    Q: What does the presentation at ASCO mean to you?

    A: “It’s one of the most gratifying moments for a clinical investigator when we hear a trial we worked on is positive. The reason why we do clinical trials is to help our patients. So have a positive trial and especially with an agent that you have worked on for years, and you have been very involved in the trial for a long time, not only in accruing patients, but also in the design and the conduct and oversight of the study and to have a trial being positive, especially for a randomized phase III trial, is a very good feeling, and the day when you hear that the results are positive is a day that you tend to remember for a very long time because what you have worked on did not only help your own patients, but hopefully if the drug gets approved, it’s going to help many patients that you have not directly interacted with, which is I think is the most important mission of any clinical research. We are the face of the trial as clinical investigators, but we have a huge team here at Yale. A lot of coordinators, clinical research nurses, regulatory staff, and our nurse practitioners – all of them have been very important to the conduct of the trial here at Yale. This was a global study that happened in many countries, many centers, and it’s a coordinated effort. So we are presenting the data on behalf of everybody and hoping that the regulatory review will be successful, and we have another option for our patients.”

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    Yale Cancer Center/Smilow Cancer Hospital

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  • Lung infection may be less transmissible than thought

    Lung infection may be less transmissible than thought

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    Newswise — A little-known bacterium — a distant cousin of the microbes that cause tuberculosis and leprosy — is emerging as a public health threat capable of causing severe lung infections among vulnerable populations, those with compromised immunity or reduced lung function.

    Recent research found that various strains of the bacterium, Mycobacterium abscessus, were genetically similar, stoking fears that it was spreading from person to person.

    But a new study by Harvard Medical School researchers published May 22 in PNAS, calls those findings into question, offering an alternative explanation behind the genetic similarity of clinical clusters. This suggests that the pathogen may not be that prone to person-to-person transmission after all.

    “Our findings make a strong case for a different explanation behind the observed genetic similarities across strains,” said study senior author Maha Farhat, the Gilbert S. Omenn Associate Professor of Biomedical Informatics at HMS and a pulmonary disease expert at Massachusetts General Hospital. Farhat conducted the work in collaboration with Eric Rubin’s lab at the Harvard T.H. Chan School of Public Health.

    The results, Farhat added, argue against direct person-to-person transmission in clinical settings and instead point to M. abscessus infections being acquired from the home or other environmental exposures.

    In addition to having implications for the precautions that hospitals take to prevent outbreaks, it’s an important new clue into the behavior of a relatively unknown pathogen that poses serious risks for vulnerable populations.

    The research not only contributes to the understanding of M. abscessus transmission, but also suggests scientists should be cautious about assuming human transmission when they see genetic similarities in pathogens more generally, said study first author Nicoletta Commins, who conducted the research as a doctoral candidate at HMS and is now a postdoctoral fellow at the Broad Institute.

    “Our results certainly do not refute the possibility of person-to-person transmission of Mycobacterium abscessus in some cases, and more research is needed to inform best clinical practice for vulnerable patients,” she said. “However, our work supports a model in which person-to-person transmission may not be as common as it is sometimes suggested to be.”

    M. abscessus is a hardy microbe highly resistant to antibiotics and can infect the lungs of immunocompromised people. While it doesn’t pose a threat to most healthy individuals, it can cause severe infection in those with suppressed immunity or people with compromised lung function such as patients with cystic fibrosis, a genetic condition marked by recurrent lung infections and lung scarring. Notably, patients with CF who become infected with this organism become ineligible for lifesaving lung transplants.

    The earlier study that sounded the alarm about person-to-person transmission was based on genetic sequencing of M. abscessus samples obtained from cystic fibrosis patients at clinics in the United States, Australia, and Europe, including the United Kingdom. Researchers found few genetic mutations across the samples — a possible sign that the pathogen was spreading directly between humans.

    For many pathogens such as TB, for example, recent person-to-person transmission leads to only a few or no mutations between any pair of samples simply because the pathogen does not have much time to acquire genetic mutations, Farhat explained.

    “Understandably, observing the genetic similarity between M. abscessus samples caused a great deal of anxiety and fear around how these organisms could be transmitting,” she said.

    Clinicians, especially in clinics that treat cystic fibrosis patients, began taking extra precautions to avert transmission. However, follow-up investigations failed to find supporting evidence that human-to-human transmission was happening, raising questions about other possible explanations for the genetic similarities across samples.

    Farhat’s team set out to investigate a hypothesis that the samples appeared genetically similar because the pathogen was evolving at a very slow rate.

    “We thought, yeah, you observed a small number of mutations, but we don’t know how quickly these mutations are acquired, she explained. “It may be slower than we think, and links between samples that appear recent may not be.’”

    The scientists first used a large dataset of M. abscessus genomes to create a “tree of life,” a kind of genetic family tree for the bacterium.

    They looked at branches of the tree with clusters of genetically similar strains, then tried to calculate their evolutionary rate. They found that these genetically similar clusters were evolving around 10 times more slowly than typical M. abscessus strains.

    Next, they used computer modeling to determine whether the genetic similarities could be explained by the relatively small population size of these bacteria. But even when they simulated extreme population sizes, the result didn’t change. This was an indicator that the high genetic similarity is best explained by a slower evolutionary rate.

    Finally, researchers conducted experiments to see how fast different strains of M. abscessus evolved to develop resistance when exposed to antibiotics in the lab. They found that the genetically similar strains evolved much more slowly than other strains.

    “These are three separate lines of evidence supporting this idea that these clustered isolates of Mycobacterium abscessus are evolving at a slower rate,” Farhat said.

    In addition to reducing concern about person-to-person transmission, the findings provide new insight into a poorly understood pathogen.

    In particular, the results offer clues about how a bug found primarily in the environment adapts and changes after it enters the human body — information that could help scientists eventually understand how to prevent and treat infections.

    Farhat is now planning follow-up studies that would compare bacteria in the environment with samples taken from patients, to better understand why certain patients become infected.

    Authorship, funding, disclosures

    Additional authors included Mark R. Sullivan, Kerry McGowen

    Evan Koch, and Eric Rubin. The work was partly supported by the Damon Runyon Cancer Research Foundation, DRG-2415-20, with additional support from the Orchestra High Performance Compute Cluster at Harvard Medical School, funded by the NIH NCRR 1S10RR028832-01.

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    Harvard Medical School

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  • CSI Singapore researchers uncover potential novel therapeutic targets against natural killer/T-cell lymphoma

    CSI Singapore researchers uncover potential novel therapeutic targets against natural killer/T-cell lymphoma

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    Newswise — Singapore, 29 May 2023 – A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has discovered that a transcription factor, TOX2, was aberrantly increased in patients with Natural killer/T-cell lymphoma (NKTL). The increased TOX2 level leads to the growth and spread of NKTL, as well as the overproduction of PRL-3 – an oncogenic phosphatase that is a known key player in the survival and metastasis of several other types of cancers. This breakthrough discovery presents a potential novel therapeutic target to treat NKTL.

    NKTL is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) with very poor treatment outcomes in the advanced stages. It is prevalent in Asia and Latin America but rare in Europe and North America. Combined radiation therapy and chemotherapy is the consensus standard therapy for NKTL patients, however, they are also often associated with high relapse rate and serious side effects. Thus, improved knowledge of the molecular mechanism leading to NKTL progression, as well as the development of novel targeted therapy strategies, has to be addressed urgently.

    Professor Chng Wee Joo and Associate Professor Takaomi Sanda from CSI Singapore, along with Dr Ong Choon Kiat from Duke-NUS Medical School, reported their ground-breaking findings in a paper published in scientific journal Molecular Cancer on 10 April 2023. Collective efforts from Dr Jianbiao Zhou, Dr Tze-King Tan, Ms Sabrina Hui-Min Toh, Miss Sinan Xiong, and the rest of the team, have contributed to these pioneering revelations.

    Their findings are also the first to show the involvement of TOX2 and PRL-3 in NKTL. These findings were validated in both cell lines and in a large set of patient tumour samples. In addition, the team analysed the clinical features of 42 NKTL cases in an independent cohort and found that TOX2 was not only overexpressed in NKTL primary tumours, but also negatively associated with patient survival.

    Currently, there are no TOX2-specific inhibitors. As such, targeting TOX2, or its downstream PRL-3, could be a valuable therapeutic intervention for NKTL patients and warrants further study in the clinic.

    Prof Chng, who is the co-lead author of the study, said, “We have now identified novel treatment targets, TOX2 and the downstream PRL3, in NKTL, where new treatment is greatly needed. We can use different strategies to target these. Proteolysis-targeting chimera (PROTAC) targeting TOX2 to degrade TOX2 protein may be a viable NKTL therapy option. A humanised antibody, PRL3-zumab, has been approved for Phase 2 clinical trials in Singapore, US, and China to treat all solid tumours. With our findings from this study, it is definitely timely to evaluate PRL3-zumab’s effect in patient with NKTL.”

    “Overall, treatment for NKTL patients remains a challenge in the clinic. Novel insight into the molecular mechanisms of this disease would guide the development of effective targeted therapies to improve the survival of NKTL patients, especially for those refractory or relapsed cases,” said Dr Jianbiao Zhou from CSI Singapore, the first author of this study.

    Moving forward, the group is currently testing novel agents for targeting TOX2 and PRL-3 in NKTL. The long-term goal is to bring these novel agents into clinical trials.

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    National University of Singapore (NUS)

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  • Chemical ‘supercharger’ solves molecular membrane mystery

    Chemical ‘supercharger’ solves molecular membrane mystery

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    More than 60% of market drugs aimed at fighting disease target molecular proteins in the cell membranes – but techological limitations have previously limited researchers’ ability to observe these proteins in their natural environment.

    Now, scientists in the lab of Yale School of Medicine’s Kallol Gupta, PhD, have identified a class of chemicals, called “superchargers,” that gently destabilize the cell membrane while leaving cell proteins intact. The team was able to show how cell membranes regulate the speed of neurotransmitter release, a key step in central nervous system signaling.

    Traditional methods of isolating proteins from the membrane environment with mass spectrometry have damaged the proteins and their ability to bind with other molecules – including those with potentially therapeutic value. This breakthrough technology will allow scientists to screen future therapeutics precisely and directly at the point where proteins encounter new drugs.

     

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    Yale University School of Medicine

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  • Fungus puppeteers hijack zombie flies

    Fungus puppeteers hijack zombie flies

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    Newswise — In a new study published in eLife, lead author Carolyn Elya, postdoctoral researcher in the Department of Organismic and Evolutionary Biology at Harvard, reveals the molecular and cellular underpinnings behind the parasitic fungus, Entomophthora muscae’s (E. muscae), ability to manipulate the behavior of fruit flies.

    Elya first described the manipulated behavior, called summiting, in a study published in eLife in 2018. Elya, who was studying microbes carried by fruit flies while a graduate student at University of California (UC) Berkeley, set out rotting fruit to capture wild fruit flies. When she later checked to see is she had captured any, she found instead zombie flies, with a banding pattern on their abdomen, that had died striking an interesting pose. Through extraction and sequencing of DNA Elya confirmed the suspected cause, E. muscae.

    Summiting occurs at sunset when the infected flies climb to an elevated location and extend their proboscises to the surface. A sticky droplet that emerges from the proboscis adheres the fly to the surface right before the wings raise up and away from the body and the flies die.

    “The climbing is very important as it positions the fly in an advantageous location for the fungus to spread to the most possible hosts,” says Elya. “The fungus jumps to the new host by forming very specialized and temporary structures that burst through the fly’s skin and shoots spores into the environment that are only good for a handful of hours. It’s a fleeting process, so an advantageous position is everything to survival.”

    While at UC Berkeley, Elya developed a laboratory model she refers to as the Entomophthora muscae-Drosophila melanogaster ‘zombie fly’ system using the wild fungal isolate she found in her backyard. With this system, Elya could continuously infect fruit flies – a laboratory staple, as well as culture the fungus independently of the fly host in media thought to mimic the internal environment of the fly.

    Summiting has appeared several times in scientific literature, but studies had only been observations of dead house flies. No one had ever observed how flies behave in their last hours of life. Elya set out to fill this knowledge gap of what happens when flies summit by developing a high-throughput behavioral assay to automatically track hundreds of infected flies. While using this platform to monitor the behavior of flies becoming zombies, she encountered a surprise. “We found that summiting is not about climbing,” said Elya, “it’s actually this burst of locomotor activity that starts about two and a half hours before the flies die.”

    With this discovery, Elya and co-authors paired her system to create on-demand zombie flies with the lab’s powerful fruit fly genetic toolkit. With these and the author’s new behavior assay they could identify genes and neurons required for flies to summit.

    “Overall, we found the flies hormonal axes was mediating summiting behavior. When we silenced these neurons the flies were really bad at summiting,” Elya says. These neurons send projections to a neurohemal organ that produces juvenile hormone, a hormone conserved in insects. “We think the fungus is actually driving the activity of these neurons in order to drive the release of this hormone, which is causing the flies to have this burst of locomotor activity.”

    Elya and co-authors were then able to collect a behavioral dataset consisting of hundreds of infected flies, which they then used to train a computer to identify flies as they are summiting. This classifier tool enabled the team to discover that fungal cells invade the fly’s brains in an organized way, occupying specific regions of the brain during summiting.

    Interestingly, the team also discovered that the flies blood brain barrier is compromised when exposed to the fungus. Normally the neurons are protected from the blood that’s circulating through the fly’s body. The breakdown of the blood brain barrier has important consequences for what the neurons are being exposed to, potentially allowing  things that are circulating in the blood to interact with neurons in the brain, thus providing a route for modulating neural activity.

    “We think this could be important for the way that the fungus is driving behavioral changes,” Elya said, “and we actually found that you can pull blood from flies that are doing the summiting behavior, put it into naive flies and drive some of this increased locomotion. So we’ve shown that there’s at least the partial ability to recapitulate this summiting behavior just by transferring fly blood.” Elya says that these experiments show some blood-borne factors can drive summiting behavior, though it’s not yet clear what the identity of these factors are or who produces them (the fungus or the fly).

    Elya hopes to next develop transgenics to help modulate things from the fungus side in addition to perturbations that can already be made in the flies. “There are still a lot of open questions here,” she says, “what the fungus is doing is still a mystery.”

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    Harvard University, Department of Organismic and Evolutionary Biology

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  • Perfect Timing: Insights into Floral Development’s Clock

    Perfect Timing: Insights into Floral Development’s Clock

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    Newswise — Ikoma, Japan – The intricate process of flower development has long fascinated scientists seeking to unravel the mysteries behind nature’s precision timing. In a study published in the journal Plant Cell, a research team led by Nara Institute of Science and Technology (NAIST), Japan has shed light on the inner workings of floral meristem termination and stamen development, uncovering a unique mechanism driven by the interplay of genetic and epigenetic factors.

    Flowers owe their intricate structures to delicate stem cell differentiation, a process by which founder cells develop into specialized cells in floral meristems. However, the precise moment at which stem cells cease self-renewal and transform into their form remains largely unknown. Driven by a desire to decipher this critical temporal transition, the researchers turned their attention to AGAMOUS (AG), a pivotal MADS domain transcription factor governing floral meristem termination.

    Through meticulous investigations in the model plant Arabidopsis thaliana, the team discovered that AG serves as a master conductor, orchestrating gene expression through a process known as cell cycle-coupled H3K27me3 dilution. This remarkable phenomenon involves the dilution of a histone modification called H3K27me3 along specific gene sequences, effectively kickstarting gene activation. The scientists identified several key genes directly regulated by AG at various time points of this cycle.

    The study revealed a genetic network tightly controlled by AG, with genes such as KNUCKLES (KNU), AT HOOK MOTIF NUCLEAR LOCALIZED PROTEIN18 (AHL18), and PLATZ10 emerging as critical players. “By unraveling the inner workings of this regulatory circuit, we gained unprecedented insight into the intricate timing mechanisms that drive proper floral meristem termination and stamen development,” says first author Margaret Anne Pelayo.

    To unlock the secrets of this remarkable system, the researchers devised a mathematical model capable of predicting gene expression timing with astonishing accuracy. By modifying the length of H3K27me3-marked regions within the genes, they successfully demonstrated that gene activation could be delayed or reduced, confirming the influence of this epigenetic timer. The team’s findings offer a novel perspective on how nature controls the gene expression during flower development.

    Furthermore, their study identified AHL18 as a stamen-specific gene with a profound impact on stamen growth and development. Misexpression of AHL18 led to intriguing developmental defects, highlighting the gene’s vital role in ensuring proper stamen elongation and maturation. Additionally, the team discovered that AHL18 selectively binds to genes crucial for stamen growth, uncovering a new layer of regulatory complexity in flower development.

    Nobutoshi Yamaguchi, senior author of the study, opined that this research not only deepens our understanding of the mechanisms underpinning floral development but also presents a potential tool for fine tuning gene expression patterns. Manipulating the delicate balance of epigenetic modifications opens up exciting possibilities for controlling plant reproduction in a flexible and reversible manner, ultimately benefiting our food supply and agricultural practices.

    This study paves the way for further exploration of epigenetic approaches to regulate gene expression with exquisite precision. By unraveling nature’s perfect clock, scientists may one day unlock new strategies for enhancing crop productivity and bolstering plant resilience, and contribute to food security despite environmental challenges.

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    About Nara Institute of Science and Technology (NAIST)

    Established in 1991, Nara Institute of Science and Technology (NAIST) is a national university located in Kansai Science City, Japan. In 2018, NAIST underwent an organizational transformation to promote and continue interdisciplinary research in the fields of biological sciences, materials science, and information science. Known as one of the most prestigious research institutions in Japan, NAIST lays a strong emphasis on integrated research and collaborative co-creation with diverse stakeholders. NAIST envisions conducting cutting-edge research in frontier areas and training students to become tomorrow’s leaders in science and technology.

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  • Gene editing, new DNA repair methods found

    Gene editing, new DNA repair methods found

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    Newswise — (Santa Barbara, Calif.) — Gene editing is a powerful method for both research and therapy. Since the advent of the Nobel Prize-winning CRISPR/Cas9 technology, a quick and accurate tool for genome editing discovered in 2012, scientists have been working to explore its capabilities and boost its performance. 

    Researchers in UC Santa Barbara biologist Chris Richardson’s lab have added to that growing toolbox, with a method that increases the efficiency of CRISPR/Cas9 editing without the use of viral material to deliver the genetic template used to edit the target genetic sequence. According to their new paper published in the journal Nature Biotechnology, their method stimulates homology-directed repair (a step in the gene editing process) by approximately threefold “without increasing mutation frequencies or altering end-joining repair outcomes.”

    “We’ve found a chemical modification that improves non-viral gene editing and also discovered an intriguing new type of DNA repair,” Richardson said.

    Find, Cut and Paste

    The CRISPR/Cas9 method works by capitalizing on a defense technique employed by bacteria against viral attackers. To do this, the bacteria snip a piece of the invading virus’s genetic material, and incorporate it into their own in order to recognize it later. Should the bacteria get reinfected, they can target the now-familiar genetic sequences for destruction.

    In gene editing, this process uses the enzyme Cas9 as molecular “scissors” to snip sequences it recognizes, guided by the CRISPR system. This cut is also an opportunity to replace the severed genes with similar (homologous) but improved ones, utilizing the cell’s natural repair mechanisms. If successful, the cell should have modified expressions and functions thereafter.

    To deliver the repair template DNA to the nucleus of the cell where its genetic material lives, oftentimes viruses are used. While they are effective, the researchers say, viral workflows “are expensive, difficult to scale and potentially toxic to cells.”

    Nonviral templates are potentially less expensive and more scalable, although researchers still must overcome efficiency and toxicity barriers. In their study, the Richardson Lab found that introducing interstrand crosslinks into the workflow increased homology directed repair dramatically.

    “Every workflow that we have put this approach into has worked better by roughly threefold,” Richardson said.

    Interstrand crosslinks are lesions that keep the double strands of a DNA helix tethered to each other, making them unable to replicate. Cancer chemotherapies use this mechanism to interrupt tumor growth and kill cancer cells. Added to a homology directed repair template, however, these crosslinks were found to stimulate the cell’s natural repair mechanisms and increase the likelihood of editing success.

    “Basically, what we’ve done is taken this template DNA and damaged it,” Richardson said. “We’ve in fact damaged it in the most severe way I can think of. And the cell doesn’t say, ‘Hey this is junk; let me throw it away.’ What the cell actually says is, ‘Hey this looks great; let me stick it into my genome.’” The result is a highly efficient and minimally error-prone nonviral system of gene editing.

    Their discovery, like many breakthroughs in science, was actually something of a happy accident. While working to purify proteins to study DNA repair, graduate student researcher and lead author Hannah Ghasemi noted unanticipated changes to the outcomes of their experiments.

    “We were introducing these chemical modifications to the DNA templates in order to be able to pull them out of the cells and see what proteins were bound to them, and I was just checking to see if this modification had somehow affected the editing in any capacity,” she said. “I was expecting to either see no change or that it actually might have negatively affected the editing.”

    What she found instead was a positive effect, up to three times the editing activity of the uncrosslinked controls. Furthermore, the team found that even with the increase in edits — and therefore the chances for errors — there was no increase in mutation frequency. They are still investigating the specific mechanisms leading to this result, but they have ideas.

    “What we think happens is that the cell detects and tries to repair the damaged DNA that we’ve added this crosslink to,” Richardson said. “And in doing so, it delays the cell past a checkpoint where it would normally stop this recombination process. And so by prolonging the amount of time that it takes the cell to do this recombination, it makes it more likely that the edits will go to completion.” Studying this new process could also lead to a better understanding about how cells detect editing reagents and how they “decide” to accept them or not, he said.

    This method will find the most use in ex-vivo gene editing applications, according to the team, that is, in the realm of disease research and preclinical work.

    “We can more effectively knock down genes and insert things into genomes to study systems outside of the human body in a lab setting,” Ghasemi said. This development allows them to more efficiently build disease models and test hypotheses about how diseases work, which could lead to better clinical and therapeutic approaches.

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    University of California, Santa Barbara

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  • Van Andel Institute, Washington University School of Medicine in St. Louis to lead genome center under $140M NIH initiative

    Van Andel Institute, Washington University School of Medicine in St. Louis to lead genome center under $140M NIH initiative

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    Newswise — GRAND RAPIDS, Mich. (May 11, 2023) — Van Andel Institute’s Hui Shen, Ph.D., and Washington University School of Medicine in St. Louis’s Ting Wang, Ph.D., will co-lead a collaborative project supported by the Somatic Mosaicism across Human Tissues (SMaHT) Network, a new $140 million National Institutes of Health-led effort to better understand the genetic differences between individual cells and tissues in the body.

    Somatic mosaicism occurs when DNA, which houses the genetic code, accumulates slight changes throughout a person’s lifetime.

    Some variations may impede cells’ ability to function. Somatic mosaicism is a key contributor to cancer, but its role in other diseases is not well understood.

    SMaHT aims to identify and catalog these somatic variants in different individuals and enable new research into development, aging and a host of disorders.

    Together, Van Andel Institute and Washington University will serve as one of five SMaHT-supported Genome Characterization Centers, which will conduct leading-edge genomic analysis for the network.

    Wang will serve as the project’s director; Shen will serve as co-director. The project is supported by a $15 million grant from the NIH Common Fund as part of SMaHT.

    “We all carry such genetic mosaicism in our bodies, but the extent and implications of these variations remain unclear. Establishing an accurate picture of its role in the body is a massive undertaking that only can be achieved through collaboration,” Shen said. “I am thrilled to partner with Dr. Wang and the SMaHT Network, and look forward to contributing to a fuller understanding of this important and yet very much uncharted aspect of our cells.”

    In total, the NIH Common Fund issued 22 awards to establish the SMaHT Network. The project is akin to other large-scale NIH-supported projects such as the Human Genome Project, a 13-year endeavor that resulted in the first full blueprint of the human genome. 

    Shen is an internationally recognized expert in bioinformatics and epigenetics, the study of changes to DNA that do not alter the DNA sequence itself. She was a long-time member of The Cancer Genome Atlas (TCGA), an NIH-led collaborative effort to molecularly map 33 different cancer types. TCGA ended in 2018 with the publication of its Pan-Cancer Atlas, a comprehensive resource for scientists seeking to understand how and why cancer develops. Shen is a current member of the National Cancer Institute’s Genome Data Analysis Network (GDAN), a successor to TCGA that develops new tools to assist in the analysis of data.

    Research reported in this publication is supported by the NIH Common Fund under award no. UM1DA058219. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

     

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    ABOUT VAN ANDEL INSTITUTE Van Andel Institute (VAI) is committed to improving the health and enhancing the lives of current and future generations through cutting-edge biomedical research and innovative educational offerings. Established in Grand Rapids, Michigan, in 1996 by the Van Andel family, VAI is now home to more than 500 scientists, educators and support staff, who work with a growing number of national and international collaborators to foster discovery. The Institute’s scientists study the origins of cancer, Parkinson’s and other diseases and translate their findings into breakthrough prevention and treatment strategies. Our educators develop inquiry-based approaches for K-12 education to help students and teachers prepare the next generation of problem-solvers, while our Graduate School offers a rigorous, research-intensive Ph.D. program in molecular and cellular biology. Learn more at vai.org.

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  • Virginia Tech researchers join together on cancer prevention, diagnosis and treatment

    Virginia Tech researchers join together on cancer prevention, diagnosis and treatment

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    May is a month to recognize the importance of cancer research, with both Brain Tumor Awareness Month and National Cancer Research Month taking center stage. Virginia Tech’s Fralin Biomedical Research Institute at VTC is dedicated to advancing our understanding of cancer and developing new ways to treat and prevent it.

    Teams of investigators are working to uncover the molecular mechanisms that drive cancer growth, migration, and metastasis. They are tackling a range of cancers, from childhood cancers to breast cancer to glioblastoma, one of the deadliest forms of brain cancer. Scientists are not just looking for new treatments, but working to make existing treatments more effective by making cancer cells more vulnerable and developing entirely new treatments that can halt cancer in its tracks and prevent its return.

    • Preventing the spread of cell death after injury – Robert Gourdie’s lab tests new compounds targeting connexin channels for therapeutic use in wound healing, reducing scarring following breast reconstruction surgery, as well as applications to treat glioblastomas and drug-resistant cancers.
    • Developing new cancer therapies – Samy Lamouille’s lab studies how cancer cells communicate; he is developing novel therapeutic strategies to target these communication mechanisms to prevent metastases in human cancer progression.
    • Connecting scientific disciplines to cure cancer – Carla Finkielstein studies the molecular clocks that instruct cells when to grow, divide, and die, and how they’re impaired in cancer cells. Her research offers a foundation for the emerging field of chronotherapeutics.
    • Understanding health impacts of cancer diagnosis – Warren Bickel studies how a cancer diagnosis and an individual’s ability to think about and plan for the future affects their health.
    • Tracking fluid flow to understand cancer, aging and women’s health – Jenny Munson studies how cancer increases fluid flow between cells, altering how tumors respond to drug therapies. She is working to commercialize some of her findings in Cairina Inc., a startup biotech company whose technologies will allow clinicians to better fight cancer and deliver personalized medicine by mapping individual tumors.
    • Finding new therapies to fight pediatric brain cancer – At the Fralin Biomedical Research Institute at VTC labs at Children’s National Research Institute in Washington, D.C., Jia-Ray Yu is seeking better understanding and therapies surrounding pediatric midline glioma, and Kathleen Mulvaney is exploring cellular communication to find better cancer treatments.

    But we don’t work alone. At the Virginia Tech Cancer Research Alliance, we are collaborating with cancer scientists from across multiple universities and health centers to introduce innovative preventions, diagnostics, and therapeutics for a variety of cancers. On May 25, the second annual Virginia Tech Cancer Research Alliance Retreat will be held at the Children’s National Research and Innovation Campus in Washington, D.C., where alliance members will share their research, forge new collaborations, and learn from keynote speakers spanning veterinary and human oncology and biomedical cancer research.

    About the Fralin Biomedical Research Institute at VTC

    The Fralin Biomedical Research Institute at VTC is one of the nation’s fastest-growing academic biomedical research enterprises and a destination for world-class researchers. The institute’s Virginia Tech scientists focus on diseases that are the leading causes of death and suffering in the United States, including brain disorders, heart disease, and cancer. Since its founding in 2010, the research institute has experienced unprecedented growth: doubling its enterprise and lab facilities in Roanoke, while also investing in brand-new laboratories on the Children’s National Research & Innovation Campus in Washington, D.C.

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    Virginia Tech

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  • High School Students Learn the Basics of Base Editing to Cure “GFP-itis”

    High School Students Learn the Basics of Base Editing to Cure “GFP-itis”

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    Newswise — Genome editing is used to modify the genes of living organisms to elicit certain traits, such as climate-resilient crops or treating human disease at the genetic level. It has become increasingly popular in agriculture, medicine and basic science research over the past decade, and will continue to be relevant and utilized well into the future. Given this prevalence, researchers at the University of California San Diego have started an outreach program that introduces genome-editing technologies to high school students.

    Assistant Professor of Chemistry and Biochemistry Alexis Komor, and Ph.D. candidates Mallory Evanoff and Carlos Vasquez, designed the Genome Editing Technologies Program as a way to educate students on base-editing technologies, expose them to scientists from diverse backgrounds and invite questions about college, professional development, and the everyday life of a graduate student or faculty member within academia. The program is detailed in April 20 issue of The CRISPR Journal.

    Base editors enable scientists to introduce point mutations at targeted sites in the genome of living cells with high efficiency and precision and, thus, have the therapeutic potential to treat thousands of human genetic disorders. Proof-of-concept studies have already demonstrated this technology’s potential in cell therapies and in treating progeria, sickle cell disease and liver diseases.

    “As we were testing out some of these tools, we asked ourselves, how do we make base editors accessible to high schoolers? How do we make this process really visible?” said Evanoff.

    Komor’s team generated a base-editing reporter system using E. coli bacteria. In this system, base-editing activity results in the expression of green fluorescent protein (GFP). The team installed a mutation in the bacterium’s GFP gene to remove its fluorescence. To emphasize the connection to genetic diseases, this phenotype is called “GFP-itis,” and students are tasked with “curing” the bacteria. Using base-editing technology, students correct the mutation back to wild-type, resulting in bacterial cells that fluoresce green.

    The program happens over three days, creating a more meaningful partnership with the school and building a better foundation of trust with the students. “We wanted the students to get to know us better and feel comfortable asking questions about a career in STEM,” said Komor. “A popular question is simply, ‘How do I get into undergraduate research?’ One of the students in the first school we visited, Sage Creek High School, is actually an undergraduate researcher in our lab now.”

    That student is Preety Iyer, a first-year human biology major, who recalled Komor’s visit to her high school as “an amazing opportunity to get hands-on experience with gene-editing technology. It seemed like an intangible concept to me when I was learning about it in my biology classes. Being walked through the entire process and being able to do it myself strengthened my understanding of DNA and gene editing.” 

    Iyer plans to become a doctor working with patients who have rare genetic disorders, and she’s excited to gain more valuable hands-on experience in Komor’s lab: “I’ve been able to use equipment and practice techniques, like flow cytometry and plasmid preparation, that other students don’t get to use until later in their academic careers.” 

    So far, the Genome Editing Technologies Program has visited three local high schools. The schools have had well-developed science classes and much of the equipment needed to run the experiment. The majority of students had also heard of or learned about genome engineering before. Now that Komor’s team has run the program a few times and solicited feedback from students, they hope to expand to schools without such robust science programming. 

    “My high school background in science wasn’t strong in large part because of the lack of mentorship,” said Vasquez. “It’s important to us to reach students who may not have even considered a career in STEM or medicine. To look in their eyes and instill confidence, to show we believe in them — having someone like that when I was in high school would have made a world of difference.”

    The make the experiment as accessible as possible, the team has simplified the base-editing experiment and provides all the necessary equipment. Accessibility also means making the program available to other institutions that may want to implement something similar. Interested scientists or instructors can order plasmid materials from AddGene, a worldwide nonprofit plasmid repository. These plasmids are the DNA needed to make the GFP-itis cells, as well the plasmids needed to as “cure” GFP-itis.

    The goal of the program is not only to make base editing accessible to high school students, but also to encourage critical thinking and reflect on base editing in social and cultural contexts. Komor’s team asked students to think about the difference between a disease and a trait and to consider the implications of germline genome editing, in which edits are inherited by all future descendants of the edited individual, regardless of whether those descendants consent to the procedure.

    “The ethical discussion is what hits a home run with the students,” said Vasquez. “They’ll be responsible for future gene-editing policies. It’s interesting to see them thinking about the ethical side of science.”

    “We’ve had some really good discussions about what is a disease and what is a trait,” stated Evanoff. “If we have the ability to make genetic-disease corrections, who will be able to afford those treatments? Where does the equitability lie in this technology? We don’t have the answers to that. I say to students, ‘That’s going to be your job to figure out!’”

    This research was supported by the National Science Foundation (MCB-2048207), the National Institute of General Medical Sciences (T32 GM007240-41), the National Institute of Health (T32 GM112584), the Howard Hughes Medical Institute (GT13672 and the Gilliam Fellowship Program) and the National Academies of Sciences, Engineering, and Medicine Ford Foundation Predoctoral Fellowship Program.

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    University of California San Diego

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  • Reviving exhausted T cells to tackle immunotherapy-resistant cancers

    Reviving exhausted T cells to tackle immunotherapy-resistant cancers

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    Newswise — LA JOLLA, CALIF. – May 03, 2023 – When the cells of our immune system are under constant stress due to cancer or other chronic diseases, the T cells of the immune system shut down in a process called T cell exhaustion. Without active T cells, which kill tumor cells, it’s impossible for our bodies to fight back against cancer. One of the biggest goals of immunotherapy is to reverse T cell exhaustion to boost the immune system’s ability to destroy cancerous cells.

    Researchers at Sanford Burnham Prebys studying melanoma have found a new way to make this happen. Their approach, described in Cell Reports, can reduce T cell exhaustion even in tumors that are resistant to clinically approved immunotherapies. It can also help T cells from becoming exhausted.

    “Slowing or reversing T cell exhaustion is a huge focus in cancer research, and many researchers are working on different ways to accomplish this,” says first author Jennifer Hope, Ph.D., who completed this research as a postdoctoral researcher at Sanford Burnham Prebys and is now an assistant professor at Drexel University. “This new approach could be a viable treatment on its own, but it also has tremendous potential to work synergistically with existing therapies.”

    Although there are established immunotherapies that target T cell exhaustion, the new approach is unique in that it targets several different aspects of the process at once. This means that it could help people overcome resistance to various anti-cancer immunotherapies that are currently available.

    “One of the foundational ideas of modern cancer treatment is not relying on a single therapy, since this can cause the cancer to become resistant to that treatment,” says senior author Linda Bradley, Ph.D., a professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. “The more tools at our disposal to slow down or reverse T cell exhaustion in different ways, the better chance we have of improving precision medicine and helping more people with cancer benefit from immunotherapy.”

    Their approach hinges on a protein called PSGL-1, which is found in most blood cells. By studying mice with a genetic deficiency in PSGL-1, the researchers determined that this protein helps facilitate T cell exhaustion, a major roadblock to effective anti-cancer immunity.

    The researchers then used an antibody to block the activity of PGSL-1 in mice with immunotherapy-resistant melanoma. They found that targeting PSGL-1 slowed the process of T cell exhaustion and helped exhausted T cells switch back into functioning T cells. These two effects significantly reduced tumor growth in the mice.

    “One of the things that makes this approach unique compared to existing immunotherapies is that it directly alters the way T cells become exhausted and helps them regain their function,” says Hope. “I think this is going to be crucial in terms of its translational potential.”

    The researchers were also able to replicate this effect in mice with mesothelioma, suggesting that the approach could be applicable to a wide range of cancers. Although the treatment they used in this study is not yet suited for clinical use in humans, the overall approach of using antibodies or recombinant proteins for immunotherapy is well established. This means that translating these results for people with cancer may just be a matter of time and testing.

    “Once we’ve done all the necessary science, this could be really valuable, or even lifesaving, for a lot of people with cancers that are resistant to current treatments,” says Bradley. “We still have a long way to go, but I’m optimistic that we’re onto something game-changing here.”

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    Additional authors on the study include Dennis C. Otero, Eun-Ah Bae, Christopher J. Stairiker, Ashley B. Palete, Hannah A. Faso, Michelle Lin, Monique L., Henriquez, Sreeja Roy, Xue Lei, Eric S. Wang, Savio Chow, Roberto Tinoco, Kevin Yip, Alexandre Rosa Campos, Jun Yin, Peter D. Adams and Linda M. Bradley, Sanford Burnham Prebys; Anjana Rao and Hyungseok Seo, La Jolla Institute for Immunology; and Gregory A. Daniels, Moores Cancer Center at UC San Diego Health.

    The study was supported by grants from the American Cancer Society (PF-20-113-01-LIB), the National Institutes of Health (T32 AI125209, R01 AI106895, R21 CA249353, R21 CA216678, R03 CA252144, R01 AI040127, R01 AI109842, P30 CA030199), the Melanoma Research Alliance (MRA 696326), the Department of Defense (W81XWH-20-1-0324), the American Association of Immunologists, the San Diego Cancer Centers Council (C3 2018), the Association of Immunologists Careers in Immunology Fellowship Program, and was supported in part by the following Sanford Burnham Prebys Core facilities: Flow Cytometry, Vivarium, Histology, Bioinformatics, Proteomics, and Cancer Metabolism.

    The study’s DOI is 10.1016/j.celrep.2023.112436

    About Sanford Burnham Prebys

    Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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