Investigating Cellular Communication in the Tumor Microenvironment in Pancreatic Cancer

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PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) 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 PDA, 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 PDA, Hedgehog (HH) signaling functions in a paracrine manner, whereby tumor cells produce HH ligands and signal to CAFs via the canonical HH receptor PTCH1, leading to downstream pathway activation. There have been contradictory genetic and pharmacologic studies in mouse models, as well as disappointing clinical trials with HH pathway inhibitors, indicating the role of HH signaling in PDA is highly complex and context dependent. This proposal aims to uncover two key aspects of HH signaling in PDA: a) HH-dependent alterations in the immune landscape through fibroblast-immune cross talk (Aim 1), and b) HH-dependent changes in endothelial cell gene expression and function through fibroblast-endothelial cross talk (Aim 2). I hypothesize that combined targeting of HH signaling in combination with the immune response or the vasculature will be required to effectively treat PDA. Our preliminary data indicate that Slit2, which regulates angiogenesis, is reduced during HH pathway inhibition in PDA. Previous work showed that epithelial Slit2 deletion promotes neural invasion and metastasis in PDA. However, I find the majority of Slit2 is produced by fibroblasts, while Robo receptors are expressed in endothelial cells. In Aim 3 of this proposal, I will determine the fibroblast-specific contribution of Slit2 to pancreatic angiogenesis and tumor growth. Overall, the proposed experiments will provide a fundamentally new understanding of cellular cross talk within the pancreatic TME, including addressing fibroblast-immune and fibroblast-endothelial communication as well as a specific investigation of SLIT-ROBO signaling in pancreatic cancer. The mentored phase of this award will be overseen by Drs. Allen and Pasca di Magliano at the University of Michigan (UM). I have developed an additional advisory team to include internationally known leaders in the fields of cancer biology (Dr. Andrzej Dlugosz), endothelial biology (Dr. Jason Spence), and immunology (Dr. Bethany Moore). Combined, this mentorship team has set forth a career development plan focused on research, collaboration, presentations, mentorship, grantsmanship, and the furthering of management skills required to successfully lead an independent research laboratory.