# Targeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated Thrombosis

> **NIH NIH U01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $855,078

## Abstract

SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates of all cancers, and the
highest rate of thromboembolic complications. The prothrombotic potential of PDAC has been directly linked to
high-level expression of Tissue Factor (TF) by PDAC tumor cells that drives exuberant thrombin activity in
circulation and in the tumor microenvironment. This proposal is based on evidence that aggressive tumor
progression and thrombophilia in PDAC are integrally linked via key bi-directional mechanisms promoting
tumor growth and procoagulant potential. Preliminary data suggests that high-level tumor cell TF activity leads
to thrombin/PAR-1 signaling in PDAC tumor cells and cancer-associated fibroblasts (CAFs), driving local
production of the plasminogen activation (PA) system components, urokinase plasminogen activator (uPA) and
receptor (uPAR). Initial results also indicate that the PA system is a central player driving the bi-directional
mechanisms of PDAC tumor progression and venous thromboembolic complications. These findings support
the central hypothesis that targeting PA system components will limit PDAC progression as well as
simultaneously and paradoxically suppress PDAC-associated thrombophilia. The proposed studies will directly
define the feed forward mechanisms linking the PAR-1/uPA/uPAR axis to PDAC tumor growth and invasion
and will also identify the feedback mechanisms by which uPA/uPAR/plasminogen drive thrombophilia in PDAC.
This consortium is a collaboration of experts in the basic and clinical sciences of hemostasis, tumor biology,
and bioengineering. The proposed studies will use multiple innovative approaches, including analysis of de
novo PDAC in unique genetically-modified mice, a cutting-edge 3D biomimetic culture system, novel
pharmacological tools, and translational patient-derived xenograft models to analyze human tumor cells and
CAFs. This powerful collection of expertise and reagents will be used to test the following specific hypotheses:
(1) PAR-1-driven expression of uPA and uPAR in PDAC tumors promotes cancer progression, and drives
thrombosis by mediating the release of tumor-cell associated TF procoagulant activity that increases circulating
procoagulant activity; (2) tumor cell-intrinsic PAR-1 activity supports PDAC invasion through induction of
uPA/uPAR, while PAR-1 signaling by CAFs drives uPA/uPAR-mediated tissue remodeling associated with
advanced PDAC; and (3) therapies targeting PA either alone or in combination with anticoagulation will
significantly impede both PDAC tumor progression and the associated thrombophilia. The proposed studies
will provide novel insights into the contribution of PAR-1/uPA/uPAR to PDAC pathobiology, illuminate key
mechanisms coupling the PA system to PDAC-associated thrombophilia, and provide essential proof-of-
principle data in experimental animals and with patient-derived material to facilitate translation of findings into
new treatments for PDAC and canc...

## Key facts

- **NIH application ID:** 10022502
- **Project number:** 5U01HL143403-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Melissa L. Fishel
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $855,078
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022502

## Citation

> US National Institutes of Health, RePORTER application 10022502, Targeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated Thrombosis (5U01HL143403-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10022502. Licensed CC0.

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