Investigating the role of RUNX2 activation across cancer evolution in lung adenocarcinoma

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Project Summary Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death; however, only a subset of patients are eligible for targeted therapies based on the presence of mutations in certain oncogenic drivers. In addition, many therapeutic approaches target cancer-initiating events, yet tumor cells acquire alternative dependencies during tumor progression. In this proposal, I aim to interrogate tumor progression in a genetically engineered mouse (GEM) model of lung adenocarcinoma termed the KP (KrasG12D/+; p53f/f) model, which faithfully recapitulates features of human disease. Transcriptional dysregulation occurs across KP tumor progression and is not explained by the acquisition of somatic mutations, suggesting that tumor evolution is driven predominantly by epigenetic mechanisms. In previous work leveraging single-cell chromatin profiling, I determined that KP tumors were marked by substantial epigenetic intratumoral heterogeneity. Interestingly, I found that late-stage populations of tumor cells exhibited progressive activation of RUNX2 transcriptional activity. In addition, RUNX2 activated cells have increased chromatin accessibility surrounding genes involved in extracellular secretion; however, the mechanism(s) by which RUNX2 alters chromatin state and gene expression programs is not well-established. Based on this and other data, my central hypothesis is that RUNX2 functions as a master regulatory transcription factor during late-stage tumor progression that aberrantly initiates gene programs that serve to i) reshape the local tumor microenvironment, ii) facilitate differential stromal/immune composition, and iii) contribute to increased intratumoral heterogeneity. My first aim will interrogate the global chromatin changes and identify RUNX2-associated cofactors in RUNX2- activated cells. The second aim will specifically focus on the role of RUNX2 activation on the remodeling of the local tumor microenvironment. The third aim will more broadly assess the spatial localization of heterogeneous gene expression programs in late-stage cancer cells. This proposal seeks to build on results generated during my postdoctoral training and will serve as the initial focus of my independent research group. My background in cancer biology and epigenetics from my graduate school training, paired with my extensive expertise in GEM models and epigenomic technologies from my postdoctoral training, positions me for a successful transition to independence. As part of this grant, I will assemble an advisory team at my institution to support my transition and career development training activities outlined in this proposal. I will take advantage of the varied resources at my postdoctoral institutions and the institution where I secure an independent position to develop skills related to mentorship, communication, and research ethics. Overall, the outlined training plain in this proposal will greatly support my continued development, with the goal of making substantial contributions in the fields of epigenetics and cancer biology.