Dr. von Diezmann [The Mark Foundation for Cancer Research Fellow] studies how cells control the pathways used to repair DNA. Errors in DNA repair contribute to the development of many cancers, such as breast, ovarian, and pancreatic cancers. Dr. von Diezmann will explore the basic principles governing the DNA damage response by examining how a specific subtype of homologous repair enzymes functions in reproductive cells of the model organism C. elegans. Her project will provide mechanistic insight into how changes in the liquid-like organization of proteins at sites of DNA damage regulate repair, supporting the development of novel chemotherapies that modulate the DNA damage response.

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.

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.

Dr. Zhang [Merck Fellow] aims to address what information is sensed and relayed by sensory nerve fibers within the pancreas. Internal organs receive sensory nerve fibers that constantly monitor their conditions but the exact mechanism for this type of sensation is understudied. As an organ that is instrumental to blood glucose regulation and food digestion, the pancreas receives a host of different sensory nerve fibers, but the information conveyed by these fibers and their function are still yet to be precisely defined. Interaction between sensory nerve fibers and the pancreas enables rapid detection of changes in metabolic states and may constitute an important feedback mechanism complementary to the well-defined humoral regulation. Local sensory fibers are also involved in cancer progression and decoding of the sensory information would facilitate early diagnosis of pancreatic cancer.

Dr. Zhang is developing small molecules that promote targeted protein degradation in human cancers. Conventional small molecule anticancer drugs act by directly inhibiting the functions of proteins. Although targeted cancer therapies have been successful in recent years, many oncogenic proteins are still considered “undruggable” because the conventional drug design strategy fails to interfere with these proteins. One way to target “undruggable” oncogenic proteins may be to create a new type of small molecule that delivers these proteins to the cellular degradation system, thereby promoting their destruction. By integrating chemical tools, proteomic platforms, and molecular biology approaches, Dr. Zhang aims to develop protein degraders as a new drug modality to expand treatment opportunities in human cancer.

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.

Antibodies, vaccines, checkpoint inhibitors, and CAR-T cells have all been successful in leveraging the immune system against disease, but these treatment strategies still have limitations. Dr. Zhou is designing new macromolecules to direct the immune response to cancer. She plans to engineer dynamic, functional proteins that respond to specific protein post-translational modifications, conformations, or complexes. She hypothesizes that these conditionally activated proteins will be able to recognize cancer-specific antigens, drive protein-protein or protein-substrate interactions, or help build synthetic cell signaling pathways, and therefore can be harnessed to enact specific anti-tumor responses.