# Hostile Environments Promote Invasion and Metastasis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $311,125

## Abstract

Inflammation plays a major role in breast cancer development and progression.
Cyclooxygenase (COX)-2 and its product prostaglandin E2 (PGE2) are major mediators
of inflammation in cancer cells. In this competitive renewal application, our new
directions are built on discoveries made during the previous funding period. With
imaging we uncovered the role of COX-2 in mechanotransduction, its impact on
attracting cancer associated fibroblasts (CAFs), altering collagen fiber structure and
function, and increasing metastasis. We found that COX-2 overexpression in tumors
impacted tumor and spleen metabolism that opens the possibility of spleen dysregulation
contributing to tumors escaping immune surveillance. In our efforts to downregulate
COX-2 in tumors with siRNA delivery, we found that most nanoparticles (NPs)
significantly increased COX-2, until we developed a biocompatible translatable dextran
NP that successfully delivered COX-2 siRNA to effectively decrease COX-2 and PGE2 in
cancer cells and tumors. These observations have resulted in our three new aims that
focus on advancing our understanding COX-2 in cancer, and in developing translatable
strategies to target COX-2 and CAFs. In Aim 1 will investigate the role of COX-2 in
altering extracellular matrix (ECM) stiffness and composition, and the impact of
eliminating CAFs that are a source of COX-2, on the ECM and on tumor immune cells
and metastasis. In Aim 2 we will identify the causes of the metabolic changes in the
tumor and spleen caused by COX-2, and the effects of eliminating CAFs on tumor and
spleen metabolism, and splenocytes. In Aim 3 we will downregulate COX-2 in
established tumors with siRNA and determine the impact on the ECM, metabolism, and
immune cells. A small component of this Aim will include developing cytokine
scavenging NPs that are based on the modified dextran NP we developed. We will
evaluate the ability of these NPs to reduce cytokines in tumor interstitial fluid. The
studies will be performed with triple negative breast cancer models genetically
engineered to overexpress or downregulate COX-2 in immune suppressed and immune
competent mice. These studies may lead to ECM modification strategies, including CAF
elimination, to alter ECM stiffness to reduce cancer aggressiveness, and may result in
new metabolic targets and biomarkers for immunotherapy, as well as new strategies to
convert an immune suppressive tumor microenvironment into an immune active one.
!

## Key facts

- **NIH application ID:** 9895166
- **Project number:** 2R01CA082337-16
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Zaver M. Bhujwalla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $311,125
- **Award type:** 2
- **Project period:** 1999-07-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895166

## Citation

> US National Institutes of Health, RePORTER application 9895166, Hostile Environments Promote Invasion and Metastasis (2R01CA082337-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895166. Licensed CC0.

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