Investigating Cellular Communication in the Tumor Microenvironment in Pancreatic Cancer

Henry Ford Health System, Detroit MI

Investigators

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Abstract

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths world-wide by 2030, largely due a lack of effective treatments. A major barrier to successful therapy is the abundant fibrotic reaction in PDAC, which includes cancer-associated fibroblasts (CAFs). While many pancreatic tumors are hypovascularized, endothelial cells regulate immune maturation and infiltration, tumor cell metabolism, and metastatic dissemination. In PDAC, SLIT-ROBO signaling was recently identified as frequently mutated. There have been contradictory genetic and pharmacologic studies in mouse models, indicating the role of SLIT-ROBO signaling in PDAC is highly complex and context dependent. Our preliminary data indicate that SLIT2 inhibits angiogenesis in human endothelial cells in vitro. Previous work showed that epithelial Slit2 deletion promotes neural invasion and metastasis in PDAC. However, we find the majority of Slit2 is produced by fibroblasts, while Robo receptors are expressed in endothelial cells. This proposal aims to uncover two key aspects of SLIT-ROBO signaling in PDAC: a) fibroblast secreted SLIT2 (Aim1) and SLIT3 (Aim2) -dependent impacts on the PDAC TME. In Aim 3 of this proposal, I will determine the fibroblast-specific contribution of dual SLIT2 and SLIT3 deletion in primary human CAFs to angiogenesis and tumor cell growth using a novel multicellular co-culture approach. Overall, the proposed experiments will provide a new understanding of the SLIT-ROBO dependent cellular cross talk within the pancreatic TME.