Defining epigenetic signaling to reshape pancreatic tumor microenvironment

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT The 5-year survival of pancreatic cancer patients remains at 10% primarily due to the tumor resistance to standard chemo and immunotherapies. The profound immunosuppressive tumor microenvironment contributes to treatment resistance. Notably, 82% of the neoadjuvant-treated pancreatic cancers carry loss of function mutations for KMT2D, a histone modification enzyme. Epigenetics is known to impact cancer cell behavior. However, how tumor cell-intrinsic epigenetic alterations modulate the pancreatic tumor microenvironment remains elusive. The long-term goal is to develop new treatments to convert pancreatic cancer to an immunologically hot tumor and improve the efficacy of immunotherapy and patient survival. The overall objectives in this application are to 1) determine the impact of KMT2D signaling on the tumor microenvironment and 2) characterize the mechanisms by which KMT2D regulates activin A expression. The central hypothesis is that upregulation of activin A upon KMT2D loss in pancreatic cancer reprograms cancer- associated fibroblasts and immune cells to promote a pro-tumoral immunosuppressive microenvironment. The rationale for this project is that the knowledge of the mechanisms by which KMT2D regulates the tumor microenvironment will pave the way for future preclinical and clinical development of new strategies to treat pancreatic cancer. The central hypothesis will be tested by pursuing three specific aims: 1) Elucidate the impact of KMT2D signaling on the immune composition in the tumor microenvironment; 2) Define the regulation of heterogeneous cancer-associated fibroblasts by KMT2D signaling; and 3) Determine the molecular mechanisms of activin A regulation by KMT2D in pancreatic cancer. Under the first and second aims, we will use our established pancreatic cancer genetic mouse models with pancreas-specific inactivation of KMT2D to determine the impact of KMT2D signaling on the differentiation and activation of cancer- associated fibroblasts, macrophages, and T cells, and ligand-receptor interactions in the tumor microenvironment and the underlying mechanisms. Single-cell RNA sequencing technology, mass cytometry, and multiplex fluorescent immunohistochemistry will be used. For the third aim, we will characterize the interactions between KMT2D and co-factors and the mechanisms of KMT2D-mediated regulation of activin A transcription and enhancer activity using ChIP-seq, BruUV-seq, and functional luciferase reporter assays. The research proposed in this application is innovative because it focuses on a novel concept that epigenetic signaling from tumor cells remodels the tumor microenvironment and contributes to cancer progression and uses state-of-the-art animal models and approaches. The proposed research is significant because it will shed light on the mechanism of transcriptional regulation by KMT2D in pancreatic cancer and the effect of KMT2D signaling on pancreatic tumor microenvironment, which will set the stage for future preclinical and clinical development of new tumor microenvironment-targeting treatment strategies.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE The proposed project is relevant to public health because pancreatic cancer patients have a dismal chance of survival secondary to tumor resistance to standard chemo and immunotherapies because of the immunosuppressive tumor microenvironment. In this proposal, we will determine how an epigenetic regulator, KMT2D, regulates the tumor microenvironment via activin A and contributes to pancreatic cancer progression. Our project will contribute to impactful new knowledge on the influence of tumor cell-intrinsic epigenetic signaling on tumor microenvironment and tumor progression, which will pave the way for the clinical development of novel tumor microenvironment-targeting treatment in combination with chemo or immunotherapies for pancreatic cancer patients.