# The Role of Lung Resident Mesenchymal Stem Cells in Post-Chemotherapy Lung Metastases of Breast Cancer

> **NIH NIH R37** · JACKSON LABORATORY · 2021 · $384,300

## Abstract

Although chemotherapy has significantly improved the survival of breast cancer patients, treatment failure still
remains a major clinical issue worldwide. Current knowledge about treatment failure is mostly derived from
research on intrinsic and acquired chemoresistance in epithelial tumor cells. However, recent studies have
implicated a critical role for host cells (i.e., the tissue microenvironment) in building a protective “niche” for
tumor cells enabling their escape from chemotherapeutic treatments. Notably, the host regenerative response
upon chemotherapy “injury”, which is regarded as a host intrinsic mechanism to repair damaged tissues, may
be exploited by tumor cells for their local recurrence or distant metastases. The proposed study will build on
our extensive experience in the study of tumor-stroma interactions in breast cancer metastasis, and will
investigate the poorly explored question of how chemotherapy-induced changes in the lung stroma foster the
early relapse of tumor cells in the lung. Based on our previous findings that tissue resident mesenchymal stem
cells (MSCs) acquire a significantly higher potential to promote local tumor growth upon cancer therapies, we
hypothesize that systemic chemotherapy treatment stimulates regenerative responses in lung resident MSCs,
which are, in turn, utilized by drug-resistant disseminated tumor cells (DTCs) for their metastatic relapse in the
lung. By designing different chemotherapy treatment scenarios in animal models mimicking clinical situations
in human breast cancer patients, we will in Aim 1 determine how chemotherapeutic drugs cisplatin and
doxorubicin modulate the lung resident MSCs using our newly established endogenous MSC modeling
platform in mice. Subsequently, we will in Aim 2 delineate the molecular mechanisms underlying drug-activated
lung resident MSCs to support metastatic tumor growth in the lung, with a focus on the TLR4 signaling
pathway and the key wound healing cytokine osteopontin (OPN). Finally, we will in Aim 3 define the
translational potential of stroma targeting approaches using both patient-derived xenograft models and breast
cancer patient specimen analyses. We will specifically focus on the therapeutic efficacy of combining
chemotherapy with TLR4 or OPN blockage in treatment of patient-derived human basal-like xenograft breast
tumors. Further, by analyzing clinical plasma samples from human breast cancer patients, we expect to
develop plasma OPN as a biomarker to predict early metastatic relapse of breast cancer patients after
chemotherapy. Overall, our proposed study will energize an underdeveloped field of research that investigates
the impact of cancer therapeutics on the pre-metastatic microenvironment. Findings from the proposed study
will facilitate the development of clinically applicable strategies to improve treatment efficacy and prevent
metastatic relapse of breast cancer by interfering with the tissue metastatic microenvironment.

## Key facts

- **NIH application ID:** 10098015
- **Project number:** 5R37CA237307-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Guangwen Ren
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,300
- **Award type:** 5
- **Project period:** 2020-02-04 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098015

## Citation

> US National Institutes of Health, RePORTER application 10098015, The Role of Lung Resident Mesenchymal Stem Cells in Post-Chemotherapy Lung Metastases of Breast Cancer (5R37CA237307-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10098015. Licensed CC0.

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