# Role of the microenvironment in ovarian cancer metastasis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $433,904

## Abstract

PROJECT SUMMARY / ABSTRACT
Half of all ovarian cancer patients die within five years. This is largely because their tumors recur after
chemotherapy and metastasize within the intraperitoneal cavity, eventually blocking function of organs such as
the bowel. Additionally, no FDA-approved drugs block the steps of intraperitoneal metastasis. Thus, new
strategies are needed to prevent ovarian cancer metastasis. This proposal focuses on the receptor tyrosine
kinase Discoidin Domain Receptor 2 (DDR2) as a candidate target to prevent ovarian cancer metastasis for the
following reasons. First, DDR2 is overexpressed in 74% of advanced-stage, high-grade serous human ovarian
tumors and 100% of metastases. Second, patients whose tumors had higher levels of DDR2 had shorter survival
than those with lower levels of DDR2. Third, preliminary data shows that, after tumor cell injection, tumors formed
in syngeneic DDR2 knockout mice were smaller and contained less collagen (the ligand for DDR2) than those
in DDR2 wild-type mice. Fourth, promising small molecule DDR2 inhibitors have been developed that, unlike all
other receptor tyrosine kinase inhibitors, bind and allosterically inhibit the extracellular domain of DDR2. This
proposal will test the central hypothesis that DDR2 in stromal cells promotes steps of metastasis by acting
through its ligand collagen to alter the microenvironment. Aim 1 will build on strong preliminary data showing that
DDR2 in the stroma promotes metastasis by identifying the particular stromal cells (fibroblasts and mesothelial
cells) and steps in which DDR2 contributes to metastasis. This aim will make use of a large bank of human
primary omental stromal cells and ovarian tumor cells. Aim 2 will test the hypothesis that DDR2 in the mesothelial
cells, fibroblasts, or both is activated by collagen I, leading to increased matrix metalloprotease 2 activity and
fibronectin cleavage. Additionally, this aim will test the hypothesis that DDR2 regulates collagen amount and
organization in the microenvironment and will identify proteins secreted by DDR2-expressing fibroblasts that
promote ovarian tumor cell invasion. Aim 3 will assess the ability of a novel DDR2 inhibitor to enhance response
to chemotherapy, and identify tumor microenvironment components that correlate with response. In addition to
testing a novel DDR2 inhibitor in mouse syngeneic and patient-derived xenograft models of ovarian cancer, this
aim will use a novel, multi-parameter fluorescent imaging tool to define tumor/stromal cell expression patterns
and extracellular matrix signatures that correlate with treatment response in mouse and human tumors.
Completion of these aims will uncover novel mechanisms by which the tumor microenvironment contributes to
intraperitoneal metastasis and reveal new potential targets for therapy.

## Key facts

- **NIH application ID:** 10249246
- **Project number:** 5R01CA234553-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Katherine Cynthia Fuh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $433,904
- **Award type:** 5
- **Project period:** 2019-09-19 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249246

## Citation

> US National Institutes of Health, RePORTER application 10249246, Role of the microenvironment in ovarian cancer metastasis (5R01CA234553-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249246. Licensed CC0.

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