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.