Cancer immunotherapy has revolutionized the way we treat cancer; however, it is only successful in a small subset of patients. Optimally functioning CD8 T cells, the specialized killers of the immune system, are key to the success of cancer immunotherapies. While CD8 T cell function is highly influenced by their metabolism, little is understood about how metabolism changes the function of these cells. Dr. Watson hypothesizes that metabolism affects CD8 T cell function by altering how tightly its DNA is packaged (its epigenetics), leading to altered gene expression. Using a mouse model of adoptive T cell therapy, a widely used immunotherapy in humans, and epigenetic techniques, Dr. Watson proposes to uncover how metabolism influences CD8 T cell epigenetic landscapes to control their function. He plans to apply these findings to improve T cell function and enhance tumor clearance. Dr. Watson received his PhD from the University of Pittsburgh, Pittsburgh and his BS from Hope College, Holland, Michigan.

Neuroblastoma is a rare pediatric cancer that typically arises in the adrenal glands, located above the kidney. Children with high-risk neuroblastoma often have poor prognoses despite intense treatment-including maintenance treatment with retinoic acid-underscoring the need for new treatments to improve long-term outcomes. Retinoic acid, which is orally available and generally well tolerated, helps neuroblastoma cells mature (differentiate) into normal cells; however, this process is entirely reversible once the retinoic acid is withdrawn. If this differentiating effect could be made permanent with the addition of a second drug, a combination treatment with retinoic acid could become a novel method of preventing patient relapse. After testing a panel of 452 small molecule drugs, Dr. Weichert-Leahey discovered that a drug called PF-9363 accentuated the effects of retinoic acid in neuroblastoma the most. She will now study how PF-9363 functions, alone and together with retinoic acid, both in cells and patient-derived neuroblastoma models in mice. These experiments will indicate whether combinations of this new compound with retinoic acid may improve outcomes for children with high-risk neuroblastoma.

Dr. Woida studies the foodborne pathogens Listeria monocytogenes and Shigella flexneri that enter and replicate within human cells. These bacteria also directly infect neighboring cells by pushing against the host cell membrane to form long membrane protrusions that extend and eventually release the bacteria into the new cell. This process of cell-to-cell spread requires the bacteria to hijack intercellular signaling pathways to reshape the host cell membrane. These signaling pathways normally regulate human cell adhesion and motility, and their dysregulation promotes tumor growth and metastasis. Dr. Woida’s goal is to uncover the unique mechanisms by which these pathogens remodel the host cell membrane to gain insight into how the co-opted intercellular signaling pathways function under both healthy conditions and tumor progression. Dr. Woida received his PhD from Northwestern University and his BS from the University of Illinois at Urbana-Champaign.

Multiple cancers, including prostate, breast, and gastrointestinal cancers, are known to be heavily innervated. However, the role of neurons and their signaling within the tumor microenvironment remains unknown. Previous work has shown that transecting the vagus nerve can block the progression of gastric cancer, emphasizing a critical role for the vagal neurons in this disease. However, these transections produce side effects, making it a difficult strategy to translate to the clinic. Dr. Wong [Kenneth G. and Elaine A. Langone Fellow] is proposing a new method to non-invasively silence neurons within the body. Specifically, she will use ultrasound to silence specific neurons in rodent models in order to determine the impact of these neurons on animal behavior and disease physiology, including the tumor microenvironment. Dr. Wong received her PhD from the University of Texas Southwestern Medical Center and her BS from St. Mary’s University.

Genome rearrangements have been widely observed in human cancers. Recent whole-genome sequencing data has identified chromothripsis, an event that introduces massive genome rearrangements in only one or a few chromosomes through catastrophic shattering and random reattachment, as one of the most frequent genome rearrangements. Chromothripsis has been associated with poor clinical outcomes in multiple cancers, but the shattering mechanisms that induce chromosome fragmentation remain uncharacterized. Dr. Wu [Marion Abbe Fellow] aims to determine the role of cytoplasmic nucleases (enzymes that cleave DNA) in chromosome shattering and genome rearrangement, which will contribute to our understanding of chromothripsis in all cancers. She will extend this project to a mouse model of glioma to determine the effects of candidate nucleases on cancer progression. Dr. Wu received her PhD and BS from Peking University, Beijing.

CAR T cells, or genetically engineered immune cells, have transformed the treatment of cancer in recent years, achieving cures for many patients who previously faced terminal diagnoses. Despite the remarkable impact that CARs have had on patients and families, however, fewer than 5% of cancer patients currently benefit from these therapies. A major barrier to broader CAR applications lies in the identification of tumor-specific targets: only ~0.00000001% of the cell surface distinguishes tumor cells from healthy cells. To date, CARs have targeted molecules on the surface of tumor cells, but the majority of tumor-specific molecules reside within the cell, where they are inaccessible to conventional CARs. Dr. Yarmarkovich’s team has pioneered a new class of CAR T cells that are able to target key drivers of cancer. These CARs completely eradicate aggressive tumors in preclinical testing and are entering the clinic in 2025. Encouraged by this success, he has proposed three new strategies to comprehensively map the landscape of subtle molecular differences that distinguish tumor cells from healthy cells. He will map the “known unknowns” using cutting-edge technologies for characterizing the surface of tumor cells, as well as the “unknown unknowns” by harnessing the immune system’s intrinsic capacity for identifying foreign targets. The goal of this study is to significantly expand the landscape of actionable immunotherapy targets, paving the way for curative therapies that benefit a much larger population of cancer patients.

Emerging evidence underscores the profound impact of the gut microbiome, a collection of microorganisms within our digestive system, on cancer. These microorganisms collectively generate various metabolites that can significantly influence cancer progression and treatment outcomes. Dr. Zeng is employing synthetic communities and mouse cancer models to delve into the intricate connections between cancer and the microbiome. His synthetic communities, comprised of over 100 strains, allow for precise manipulation of the microbiome to elucidate the role of specific microbial metabolites in cancer. Additionally, Dr. Zeng is studying community-scale metabolism and using genetically edited strains to design synthetic communities with desired metabolic profiles. These approaches will gain valuable insights into microbiome-cancer interactions and establish a broadly applicable strategy to harness the therapeutic potential of gut microbiome. Dr. Zeng received his PhD from Princeton University, Princeton and his BS from Tsinghua University, Beijing.

In cells, DNA wraps around a protein complex consisting of proteins called histones. Chemical modifications to histones can affect gene expression, which is key to activating or suppressing cancer progression. Histone monoaminylation, in which an amine (e.g., serotonin, dopamine, or histamine) attaches itself to a histone, is a newfound type of epigenetic modification whose role remains elusive in these processes. Dr. Zhang is using chemical biology tools to study the functions of these modifications as well as their effects on other adjacent, pre-existing cancer-associated modifications. This research may establish a foundation for how this epigenetic modification regulates gene expression and offer insight into the role of amines in the progression of cancer and human neurodegenerative disorders. Dr. Zhang received his PhD from the California Institute of Technology, Pasadena and his BS from Tsinghua University, Beijing.

Cancer growth is often driven by the dysregulation of a class of proteins known as small GTPases. These proteins act as molecular "on/off" switches that regulate critical cellular processes such as cell division and movement. However, in cancer, these molecular switches often become stuck in the "on" state due to mutations that hamper GTP hydrolysis, the reaction that turns "off" the GTPase switch. One notable example is the family of GTPases encoded by Ras genes, which are mutated in 30% of all human cancers. Dr. Zhang's research aims to design small molecules that inactivate these mutant GTPases by accelerating GTP hydrolysis. His research will provide a new therapeutic mechanism for the treatment of mutant Ras-driven cancer for which no direct therapies are yet available. The design principles may also apply to the modulation of other small GTPases whose overactivation underlies cancer progression.

On the cellular level, aging manifests as cellular senescence—when cells permanently stop multiplying but do not die. Aberrant accumulation of senescent cells is thought to be a major contributor to age-dependent tissue degeneration and its associated pathologies. Elimination of senescent cells has been shown to improve age-associated tissue damage pathologies and extend healthy lifespan in mice. Senescent cells undergo extensive remodeling on their surface, including increased production of many surface proteins. Dr. Zhang [HHMI Fellow] is using a quantitative proteomics approach to investigate the mechanisms and biological consequences of cell surface remodeling in senescent cells. His goal is to identify new therapeutic targets on the senescent cell surface and develop next-generation chimeric antigen receptor (CAR) T cells and antibodies to evaluate their impact on age-related diseases. Success with this approach may have a transformative impact on treating life-threatening diseases like cancer, fibrosis, and atherosclerosis. Dr. Zhang received his PhD from Gerstner Sloan Kettering Graduate School and his BS from Sun Yat-Sen University.