PROJECT SUMMARY
The overarching goal of this research program is to identify therapeutic strategies to convert the stroma of
pancreatic ductal adenocarcinoma (PDAC) to a chemo- and immune-sensitive tumor microenvironment (TME).
PDAC is characterized by a desmoplastic stroma that facilitates tumor growth/invasion, chemoresistance of
pancreatic cancer cells (PCC), and immunosuppressive TME. Highly packed cancer-associated fibroblasts
(CAFs) and dense extracellular matrix (ECM) are hallmarks of the PDAC stroma and constitute physical drug
delivery barriers. Several stromal components have been targeted to enhance drug delivery, but recent studies
have suggested anti-tumor roles for the stroma as complete ablation of stromal components leads to more
aggressive tumors. New strategies are highly desired to reprogram stroma without compromising its anti-tumor
roles. The central hypothesis is that the coagulation system in the PDAC TME can be targeted to reprogram
PDAC stroma to overcome chemoresistance, drug delivery barriers, and immunosuppressive TME. Cancer-
associated coagulation has been reported as a key functional signaling pathway in PDAC. Notably, several
coagulation molecular targets, including thrombin, protease-activated receptor 1 (PAR1), and fibrinogen/fibrin,
have been implicated in important roles contributing to tumor progression and therapeutic resistance.
Specifically, it is hypothesized that the thrombin-PAR1 signaling axis can be targeted to suppress PCC
growth/invasion and CAF growth/fibrosis. In addition, thrombin-mediated fibrin deposition can be targeted to
suppress the drug delivery barrier and immunosuppressive TAM activities, which suppresses anti-tumor T cell
activities. This hypothesis will be tested mechanistically and evaluated for translational potential by pursuing
the following two integrated aims: Aim 1) Mechanistic Research: Determine the contribution of the coagulation
targets in the PDAC TME. Specifically, the team will determine the role of thrombin-PAR1 signaling axis to
CAF-mediated fibrosis, thrombin-mediated fibrin deposition on drug resistance, and PAR1/fibrin on the
immunosuppressive TME. Aim 2) Translational Research: Evaluate the pharmacological inhibition of the
coagulation targets. Especially, the team will expand the mechanistic understanding from Aim 1 using patient-
derived PDAC models with FDA-approved inhibitors of thrombin and PAR1, and fibrinogen depleting agents.
The effects of pharmacological inhibition will feedback to Aim 1 to delineate the efficacy of inhibiting
coagulation targets. The outcome of this research will establish a new mechanistic understanding of the role of
coagulation activities in the PDAC TME. It will determine whether blockade of the coagulation is a promising
strategy to reprogram the PDAC stroma and, ultimately, suppress PCC/CAF growth and improve drug delivery
and efficacy.