Chromatin and immune regulation of tumor growth and progression

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PROJECT SUMMARY Lung and pancreatic ductal adenocarcinomas are often diagnosed at very late stages of tumor progression when they are most aggressive and difficult to treat. Currently, very little is known about the characteristics that make up the complex tumor heterogeneity of late-stage tumors and what factors contribute to such changes in cancer cell state and disease progression over time. Investigating how the mechanisms by which these contributing factors impact tumorigenesis and tumor heterogeneity may uncover unappreciated biological processes that control tumor development. The goal of this work is to elucidate the molecular and cellular mechanisms that drive changes in chromatin state and immune response and how they shape tumor heterogeneity and tumor progression. In the F99 phase, I aim to elucidate how a novel tumor suppressor gene constrains lung tumorigenesis. My colleagues and I identified STAG2 as a tumor suppressor in a genetically engineered mouse model of oncogenic KRAS-driven lung cancer. STAG2 is a subunit of one of the two major cohesin complexes, which are implicated in regulating chromatin boundaries and gene expression. However, the mechanism by which Stag2 inactivation drives lung tumor growth is unknown. I performed chromatin accessibility profiling and gene expression analyses on STAG2-proficient and STAG2-deficient mouse lung cancer cells and have unveiled potential mediators of STAG2 function. Based on my analyses, I hypothesize that STAG2 controls genes involved in early stages of tumorigenesis by directly impacting cohesin regulation of 3D chromatin organization. Using chromatin conformation assays, I will assess how STAG2 regulates chromatin at different stages of tumor progression and how Stag2 inactivation drives lung tumorigenesis. Additionally, I will use Tuba-seq to identify key epistatic and downstream mediators of STAG2 tumor suppression and chromatin conformation assays to ascertain the STAG2-mediated mechanisms impacting lung tumor maintenance. In the K00 phase, I aim to elucidate how cancer cell state shapes pancreatic ductal adenocarcinoma (PDAC) response to T-cell mediated anti-tumor immunity. PDAC subpopulations with distinct transcriptional profiles, stromal composition, and response to chemotherapy have been previously established. However, it remains unknown whether these tumor subtypes harbor differential response to T-cell mediated immunity. To investigate how cancer cell state shapes PDAC progression by enabling evasion of cytotoxic T cell responses, I will leverage PDAC mouse models that enable the initiation of cytotoxic T cell responses at different stages of tumor progression using an inducible mouse model T cell antigen. Using longitudinal multi-omics, immunophenotyping, and tumor volume analyses, I will investigate how aspects of tumor heterogeneity contribute to mechanisms of immune evasion at various stages of tumor progression, identify key mechanistic drivers, and thus uncover novel strategies to enhance anti- tumor immune responses. Together, this body of work will elucidate principles of chromatin regulation and tumor heterogeneity that contribute to progression and immune response in lung and pancreas cancers.