Targeting fibroblast activation suppresses chemotherapy-induced pro-invasive remodeling of the extracellular matrix
- 1Tufts University
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that accounts for nearly 20% of breast cancer diagnoses. Despite recent approvals of novel therapeutic agents for TNBC, neoadjuvant chemotherapy remains part of standard of care treatment for TNBC patients. However, approximately 60% of TNBC patients who received neoadjuvant chemotherapy fail to achieve pathological complete response and face significantly elevated risks of recurrence and distant metastasis. We have shown that chemotherapy can induce significant changes in TNBC tumor extracellular matrix (ECM) that drive tumor cell invasion and may contribute to recurrence. Here, we investigate how chemotherapy drugs can impact resident fibroblasts, the major generators of ECM in the breast tissue. We find that chemotherapy activates fibroblasts and that doxorubicin specifically induces the production of pro-invasive ECM by fibroblasts via TGF-{beta}/Smad3 signaling. An FDA-approved tyrosine kinase inhibitor nintedanib suppressed doxorubicin-induced fibroblast activation and pro-invasive ECM production by fibroblasts in vitro. Additionally, in a TNBC mouse model, nintedanib reduced fibroblast activation markers in tumors, suppressed tumor cell motility in the tumor ECM, and reduced lung metastasis. These findings demonstrate a novel mechanism by which chemotherapy can induce fibroblast activation and imply that targeting fibroblast activation reduces chemotherapy-induced metastasis in TNBC.
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BibTeX
@misc{yui2026targeting,
title = {{Targeting fibroblast activation suppresses chemotherapy-induced pro-invasive remodeling of the extracellular matrix}},
author = {A. Yui and L. Peng and K. C. Lew and D. J. Landau and C. Zhang and T. J. Gerton and M. Li and S. Jullian-Guyard and M. Caron and J. P. Fatherree and R. A. McGinn and A. L. Bayer and P. L. Alcaide and C. Kuperwasser and M. J. Oudin},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749413},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749413v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Targeting fibroblast activation suppresses chemotherapy-induced pro-invasive remodeling of the extracellular matrix
AU - A. Yui
AU - L. Peng
AU - K. C. Lew
AU - D. J. Landau
AU - C. Zhang
AU - T. J. Gerton
AU - M. Li
AU - S. Jullian-Guyard
AU - M. Caron
AU - J. P. Fatherree
AU - R. A. McGinn
AU - A. L. Bayer
AU - P. L. Alcaide
AU - C. Kuperwasser
AU - M. J. Oudin
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749413
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749413v1
AB - Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that accounts for nearly 20% of breast cancer diagnoses. Despite recent approvals of novel therapeutic agents for TNBC, neoadjuvant chemotherapy remains part of standard of care treatment for TNBC patients. However, approximately 60% of TNBC patients who received neoadjuvant chemotherapy fail to achieve pathological complete response and face significantly elevated risks of recurrence and distant metastasis. We have shown that chemotherapy can induce significant changes in TNBC tumor extracellular matrix (ECM) that drive tumor cell invasion and may contribute to recurrence. Here, we investigate how chemotherapy drugs can impact resident fibroblasts, the major generators of ECM in the breast tissue. We find that chemotherapy activates fibroblasts and that doxorubicin specifically induces the production of pro-invasive ECM by fibroblasts via TGF-{beta}/Smad3 signaling. An FDA-approved tyrosine kinase inhibitor nintedanib suppressed doxorubicin-induced fibroblast activation and pro-invasive ECM production by fibroblasts in vitro. Additionally, in a TNBC mouse model, nintedanib reduced fibroblast activation markers in tumors, suppressed tumor cell motility in the tumor ECM, and reduced lung metastasis. These findings demonstrate a novel mechanism by which chemotherapy can induce fibroblast activation and imply that targeting fibroblast activation reduces chemotherapy-induced metastasis in TNBC.
ER -