# Targeting the HMGB1-TLR5 pathway to prevent senescence-induced metastasis in breast cancer.

> **NIH NIH R03** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $84,750

## Abstract

ABSTRACT
The current standard for treatment of regional breast tumors involves surgery, radiotherapy or chemotherapy.
While effective at reducing or even eliminating the primary tumor burden, chemotherapy can paradoxically
promote cancer dissemination and metastasis. Understanding the molecular mechanisms that link
chemotherapeutic treatment to metastasis in breast cancer is paramount to developing more effective
treatments and a durable response. Exposure to genotoxic stress, as elicited upon chemotherapy or
radiotherapy, can result in the engagement of a senescence program in both tumor cells and non-transformed
neighboring cells. The presence of senescent cells has recently been shown to promote aggressive traits in
cancer tumor models, including increased proliferation, enhanced angiogenesis and activation of the epithelial-
to-mesenchymal transition (EMT) program. EMT confers migratory and invasive features to cancer cells, which
facilitate their mobilization out of primary tumor sites and into circulation, favoring the metastatic process. The
secretion by senescent cells of a specific set of proinflammatory cytokines and chemokines, collectively
referred to as the SASP, is believed to mediate the detrimental effects of senescence on tumor cells. The
overarching goal of this study is to leverage our understanding of the SASP to blunt the emergence of
aggressive tumors following genotoxic treatment. Specifically, we have identified the flagellin receptor TLR5 as
a potent regulator of senescence-driven IL-6 secretion in an siRNA screen. We independently confirmed these
results, and demonstrated that TLR5 depletion blunts senescence-induced expression of diverse SASP
factors. Overall, TLR5 represents an ideal potential therapeutic target to prevent the detrimental effects of the
SASP in chemotherapy-treated breast cancer patients. We propose here to determine the contribution of TLR5
signaling to genotoxic stress-induced SASP production in breast cancer cells (aim 1), and to test the
hypothesis that blocking the TLR5 signaling pathway prevents the emergence of aggressive phenotypes in
chemotherapy-treated breast cancer (aim 2). The long-term goal of this project is to uncover the therapeutic
potential of targeting TLR5 as an adjuvant strategy to prevent the resurgence of aggressive breast tumor cells
following chemotherapy treatment.

## Key facts

- **NIH application ID:** 10877893
- **Project number:** 5R03CA269552-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Gregory David
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $84,750
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877893

## Citation

> US National Institutes of Health, RePORTER application 10877893, Targeting the HMGB1-TLR5 pathway to prevent senescence-induced metastasis in breast cancer. (5R03CA269552-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10877893. Licensed CC0.

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