# Senescent CAFs in Breast Cancer Progression

> **NIH NIH R56** · WASHINGTON UNIVERSITY · 2024 · $388,750

## Abstract

Cancer predominantly affects the elderly, with a significant incidence of breast cancer in women aged 50-70.
While cell mutations contribute to tumorigenesis, age-related changes in the tumor microenvironment,
particularly in cancer-associated fibroblasts (CAFs), which themselves are diverse subsets with distinct roles,
including inflammatory, vascular, and myofibroblast CAFs (iCAF, vCAF, and myCAF, respectively)2, may play a
crucial role. Importantly, CAF subsets display substantial variability between different tissues and even within the
same tissue3. Our study identifies senescent CAFs (senCAFs) as key players in breast cancer progression. In
exciting new data we find that 1) senCAFs are frequently found in DCIS where they predict recurrence and in
triple negative breast cancer (TNBC), estrogen receptor positive (ER+) BC, and Her2/Neu+ BC. 2) senCAFs are
restricted to the myCAF population, raising the possibility that they are a developmental endpoint and do not
simply appear stochastically in response to tissue level stress. 3) Depletion of senCAFs significantly reduces
primary tumor progression and metastasis. 4) senCAFs modify the biophysical features of the extracellular matrix
(ECM), which can impact host immune responses and tumor progression3. 5) senCAFs modify NK cell killing
activity, which supports tumor growth. Together, these data lead to our hypothesis that senCAFs alter the
biophysical properties of the ECM and immune responses to increase tumor growth and metastasis. To
address this exciting hypothesis, we will use state of the art immunological and biophysical techniques in novel
genetically engineered mouse models (GEMM) that we have built and human BC specimens in the following
Aims. 1) Determine the organ specific effects of senCAFs on metastatic BC progression; 2) Determine
how senCAFs impact ECM dynamics and tumor cell migration; and 3) Determine the impact of senCAFs
on NK cell function and BC tumor progression. Our study on senCAFs, a novel component of the breast
cancer microenvironment, may uncover critical mechanisms in breast cancer progression, guiding the
development of immunotherapeutic and senolytic strategies.

## Key facts

- **NIH application ID:** 11170331
- **Project number:** 1R56AG088264-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sheila A Stewart
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 1
- **Project period:** 2024-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11170331

## Citation

> US National Institutes of Health, RePORTER application 11170331, Senescent CAFs in Breast Cancer Progression (1R56AG088264-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11170331. Licensed CC0.

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