Epigenetic regulation of the tumor microenvironment in pancreatic cancer

• Applicant: Privatdozentin Dr. Kim Christin Honselmann
• Subject Area: General and Visceral Surgery
• Term: from 2017 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326985593

Pancreatic ductal adenocarcinoma (PDAC) contains a highly desmoplastic stroma which not only promotes aggressive local growth of the tumor but plays a key role in the failure of traditional chemotherapeutic approaches. Despite being a major component of the tumor stroma, the extracellular matrix (ECM) of PDAC has been poorly characterized. The ECM is a meshwork of cross-linked proteins that function, at least in part, as a reservoir for growth factors, cytokines and ECM-remodeling enzymes. Collectively, the proteins that make up the ECM have been termed the matrisome. The production and remodeling of the ECM, largely mediated by cancer-associated fibroblasts (CAFs), promote tumor growth and migration of cancers cells. Work by the host laboratory characterizing epigenetic regulators in pancreatic cancer has revealed an important role for the BET family of chromatin adaptors in the growth of PDAC cells and CAFs in both xenograft and genetically engineered mouse models of PDAC. Gene expression profiling of PDAC xenograft tumors revealed that BET proteins regulate the expression of a large portion of the genes that comprise the matrisome, which will be the focus of this grant proposal.Experiments in the first aim will employ an unbiased proteomic approach to define the PDAC matrisome, as well as transcriptomic analysis to determine the extent by which BET proteins regulate the expression of matrisome components. Experiments proposed in the second aim will interrogate whether pharmacological inhibition of BET proteins results in a reorganization of the ECM that can be exploited to prevent metastatic dissemination of the primary tumor and investigate if structural differences in patient samples correlate with patient outcome. The experiments proposed in this application will examine the regulation of the PDAC matrisome by BET proteins and determine whether this regulation can be therapeutically targeted to alter the biology of the tumor. This will ultimately contribute to the understanding of pancreatic cancer as a whole.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Andrew Liss, Ph.D.