# Thrombin-dependent mechanisms of pancreatic ductal adenocarcinoma disease

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $459,478

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all cancers, is rapidly becoming
the second leading cause of cancer deaths in the U.S., and is estimated to cost the health care system $2.4
billion each year. Patients with PDAC have a 5-year survival rate of 7% and that number drops to 2% for
individuals with metastatic disease. Unfortunately, there has been little progress in shifting patient outcome
over the past 40 years, highlighting the need for innovative approaches to define the molecular pathways that
influence PDAC development. PDAC can be initiated in exocrine epithelial cells that acquire an activating
mutation in the KRAS protooncogene, causing the cells to transition to pancreatic intraepithelial neoplasia
(PanIN) lesions that can progress into PDAC. A key transcriptional response to KRAS activity is increased
expression of the physiological activator of the coagulation system, Tissue Factor (TF). TF mediates
conversion of prothrombin to the active protease thrombin that in turn promotes extensive fibrin deposits within
the tumor microenvironment (TME) and activates G-protein coupled protease-activated receptors (PARs) on
target cells, including PDAC tumor cells, tumor-associated macrophages (TAMs) and cancer-associated
fibroblasts (CAFs). The scientific premise is based on a known relationship between pancreatic cancer and
high-level blood coagulation system activity, but is unique in that it will define newly discovered mechanisms of
crosstalk by which specific coagulation factors in the TME promote PDAC pathogenesis. Our central
hypothesis is that thrombin drives early PanIN development as well as advanced PDAC tumor growth and
metastasis by mechanisms linked to both fibrin matrix deposition in the TME and PAR-1 signaling on tumor
and TME cells promoting a feed forward pathway of PDAC disease. This hypothesis will be tested by utilizing
a combination of unique genetically engineered mouse models, cutting-edge pharmaceutical reagents, and
patient-derived PDAC tumor cells to pursue three Specific Aims - (1) determine how the thrombin-fibrin axis
contributes to early PanIN development and late stage PDAC tumor growth and metastasis; (2) determine the
individual mechanisms by which thrombin receptor PAR-1 signaling on tumor cells, TAMs and CAFs
exacerbates distinct aspects of PDAC pathogenesis; and (3) determine the efficacy of pharmacological fibrin
and PAR-1 inhibition in halting the progression of established mouse PDAC and human patient-derived
xenograft tumors. These studies are significant because they will (i) be the first to define the impact of
thrombin throughout PDAC disease; (ii) identify specific mechanisms of thrombin-dependent PDAC disease
progression; and (iii) provide novel opportunities to target PDAC tumors using specific state-of-the-art inhibitors
of fibrin matrix and PAR-1 signaling pathways. The discoveries made will greatly advance the understanding
of mechanisms underly...

## Key facts

- **NIH application ID:** 10017669
- **Project number:** 5R01CA211098-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Matthew J. Flick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,478
- **Award type:** 5
- **Project period:** 2017-06-19 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017669

## Citation

> US National Institutes of Health, RePORTER application 10017669, Thrombin-dependent mechanisms of pancreatic ductal adenocarcinoma disease (5R01CA211098-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017669. Licensed CC0.

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