# Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $609,743

## Abstract

Project Summary
Lung and triple-negative breast cancers (TNBCs) are leading causes of cancer-related deaths in the U.S. This
high mortality rate is largely due to their propensity to rapidly progress and metastasize. While targeted therapies
for lung adenocarcinoma have improved overall survival, similar advances in lung squamous carcinoma (LUSC)
and TNBC have been stagnant. However, for both cancer types, immune checkpoint blockade and/or
angiogenesis inhibitors improves disease control. Thus, a more complete understanding of how vascular/immune
niches within the tumor microenvironment (TME) promotes LUSC and TNBC will allow us to build upon these
advances. Our teams have recently demonstrated that LUSC and TNBC promote tumor growth and metastases
through a convergence on fibrin remodeling (Nature Communications, 2018; J Clinical Investigation, 2019) and
activation of endothelial cell wound-healing programs (Oncogene, 2019). Fibrin(ogen) that escapes leaky tumor
endothelial cells (TECs) acts as a scaffold for tumor cell motility and creates a provisional matrix for tumor
progression. Using highly integrated bioinformatics and novel LUSC models, we recently found that CCL2-
mediated recruitment of Factor XIIIA (FXIIIA)-expressing inflammatory monocytes (IMs) promotes fibrin cross-
linking, metastases and poor survival in LUSC. We also found that TEC heterogeneity (TECH) directs fibrin
accumulation through a TGFβ/miR-30c/PAI-1 signaling axis - TECs with high levels of the fibrinolysis inhibitor,
PAI-1, increase perivascular fibrin networks that support sprouting angiogenesis and tumor progression. We
have also uncovered a secondary connection between fibrin remodeling and the RNA-binding protein Quaking
(QKI) which is enriched in TECs and drives tumor angiogenesis. Silencing QKI in TECs inhibits sprouting
angiogenesis and metastases, but micro-vessel density (MVD) paradoxically increases; which we posit is due to
CXCL12-mediated sequestering of CXCR4+ IMs that initiate fibrin cross-linking. Based on these collective new
insights from our groups, we hypothesize that (i) inhibition of TEC QKI initially blocks tumor angiogenesis and
metastasis, however, a CXCL12-mediated retention of FXIIIA+ IMs promotes fibrin remodeling and rebound
angiogenesis. Additionally, we propose (ii) that TECH drives the formation of aberrant and persistent perivascular
fibrin scaffolds in LUSC and TNBC via a spectrum of TGFβ/miR-30c/PAI-1 expression. The objective of this
proposal is to elucidate how fibrin remodeling and tumor progression depend on the heterotypic relationships
between TECs and IMs, and the heterogeneity amongst TECs within the TME.

## Key facts

- **NIH application ID:** 10179715
- **Project number:** 1R01CA258451-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Andrew Carl Dudley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $609,743
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179715

## Citation

> US National Institutes of Health, RePORTER application 10179715, Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices (1R01CA258451-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179715. Licensed CC0.

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