# Leveraging the metastatic tumor stroma to limit breast cancer progression

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $458,795

## Abstract

Project Abstract
Over 297,790 new cases of invasive breast cancer diagnoses and 43,170 deaths from metastatic breast cancer
(mBC) are expected in the USA this year (SEER database). Despite advances in the treatment of localized
disease, the 5-year overall survival of patients with mBC remains at a dismal 29%. Current therapeutic strategies
primarily focus on tumor cells and neglect the important role the tumor stroma plays in cancer progression.
Underscoring the importance of the stromal compartment, stromal gene signatures can predict clinical outcomes
for breast cancer patients7. The most common site of breast cancer metastasis is the bone and unfortunately,
once the disease metastasizes to the bone, it is considered incurable and treatment is mainly palliative8. In the
bone, the tumor stroma consists of a wide array of cell types including fibroblasts, adipocytes, nerve cells,
endothelial cells, immune cells, chondrocytes, osteocytes, osteoblasts, and osteoclasts. Nearly all of these
stromal cell types has been implicated in tumor progression by directly supporting tumor cell growth, survival,
modulating the immune response to tumors, and/or driving bone loss that ignites a vicious cycle that supports
further tumor growth in the bone8. One important stromal cell that supports primary tumor progression is the
senescent cell, which was recently described as an emerging cancer hallmark9. Indeed, we demonstrated that
senescent fibroblasts drive tumor growth10 and create immunosuppressive environments11 in the primary tumor
setting through expression of p38MAPKα-dependent senescence associated secretory phenotype (SASP)
factors. Whether the same mechanisms are active in the metastatic setting remains an open question. We have
found that p38MAPKα inhibition (p38i) reduces mBC progression by targeting the metastatic stromal
compartment, but not tumor cells, in numerous preclinical models. In this proposal, we will examine how
p38MAPKα activation in the metastatic stroma contributes to tumor progression and modifies the immune
response to allow mBC to progress. We will utilize genetic and pharmacologic tools to identify the cell targets of
p38i, determine if a new stromal cell that we have identified, the senescent metastatic-associated cancer
associated fibroblast (smeCAF) contributes to cancer-induced bone loss, and determine if smeCAFs modify the
host immune response within the bone. Our goal is to understand how p38i alters the stromal compartment to
decrease mBC progression so that this knowledge can be leveraged to develop combinatorial strategies to
deploy p38i, senolytics (drugs that kill senescent cells), and immunotherapy to limit mBC progression.

## Key facts

- **NIH application ID:** 10878324
- **Project number:** 1R01CA282810-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sheila A Stewart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $458,795
- **Award type:** 1
- **Project period:** 2024-03-15 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878324

## Citation

> US National Institutes of Health, RePORTER application 10878324, Leveraging the metastatic tumor stroma to limit breast cancer progression (1R01CA282810-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10878324. Licensed CC0.

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