Dissecting mechanisms of inflammation driven cancer susceptibility in epithelial barrier tissues

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Project Summary/Abstract: Inflammation has long been known to increase risk of tumorigenesis. Epithelial barrier tissues are perpetually exposed to a myriad of environmental and inflammatory insults that necessitates robust regenerative capacity of their tissue-specific epithelial stem cells (EpSCs) to restore barrier integrity. The long term consequences of these inflammatory encounters on the tissue and EpSCs is poorly understood. Here, I seek to understand how exposure to inflammation results in epigenetic and cellular rewiring of EpSCs and their lineages in different barrier tissues and how this rewiring can be maladaptive leading to increased cancer susceptibility. The F99 phase of this proposal is focused on the mechanisms by which inflammatory experience is encoded within the chromatin of skin epithelial stem cells (EpSCs) and how inflammation-experienced skin accelerates tumor formation. I have begun to uncover the molecular mechanisms of how EpSCs acquire and maintain chromatin accessibility at key domains associated with stress response genes that contribute to an inflammatory response. My studies suggest that this phenomenon occurs through the complex and dynamic interplay between transcription factors (TFs) that are naturally present in steady state EpSCs but cannot gain access to stress response enhancers without inflammation-induced TFs. As I unearth the molecular mechanisms involved, I will interrogate how this inflammatory rewiring of skin EpSCs epigenome accelerates tumor formation as EpSCs acquire oncogenic mutations that lead to squamous cell carcinomas (SCCs), a life-threatening, metastatic cancer for which there are few effective therapies. At the completion of the F99 phase, l will have gained strong experience in in vivo high-throughput epigenetics, mouse genetics and epithelial stem cell biology, and transition to a postdoc to gain advanced expertise and training in human cancer and immunology. For the K00 phase, I will shift my focus to how inflammatory experience can reshape colonic epithelium composition in the gut and how this reshaping, along with EpSC epigenetic rewiring, results in colorectal cancer (CRC). Interestingly, colitis can result in colitis-induced CRC that follows a different molecular driven pathogenesis than traditional CRC. Thus, to further understand the mechanisms that drive colitis-induced CRC, I plan to expand my technical expertise to include colitis-induced CRC modeling, single-cell epigenomic and transcriptomic techniques, genetic screening and human organoid modeling. These new approaches coupled with my already strong background in molecular biology and high-throughput genomic analyses, will allow me to address the most pressing and challenging issues in inflammation experience and cancer biology today. With the aid of this award, I intend to continue my research contribution and gain the necessary experience to become an Assistant Professor at a major academic institution. There I will head my own lab and guide my students in epithelial cancer research with the ultimate goal of finding new targets to treat these aggressive cancers.