Inflammation awakens dormant cancer cells by modulating the epithelial–mesenchymal phenotypic state
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PNAS_manuscript_09032025.pdf
Description
Accepted version
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5.71 MB
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Author(s)
Zhang, Jingwei
Zhang, Jingwen
Han, Longfei
Wu, Shiyi
Li, Jie
Eaton, Elinor Ng
Yuan, Bingbing
Reinhardt, Ferenc
Li, Hao
Strasser, Patrick C.
Date Issued
September 3, 2025
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Citation
J. Zhang,J. Zhang,L. Han,S. Wu,J. Li,E.N. Eaton,B. Yuan,F. Reinhardt,H. Li,P.C. Strasser,S. Das,J. Liu Donaher,M.I. Khalil,H. Jiang,A. Deuschel,D. Lin,C. Sebastiany,M. Maranga,S. Shubitidze,[...] & R.A. Weinberg, Inflammation awakens dormant cancer cells by modulating the epithelial–mesenchymal phenotypic state, Proc. Natl. Acad. Sci. U.S.A. 122 (36) e2515009122 (2025).
Version
Author's final manuscript
Abstract
The awakening of dormant disseminated cancer cells appears to be responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, nonproliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, lung inflammation induced by the chemotherapeutic agent bleomycin effectively awakens dormant cancer cells, providing useful models for studying metastatic awakening. Mechanistically, the awakened cells shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire tumorigenicity and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their tumor-initiating ability, doing so without ongoing heterotypic signaling from the lung microenvironment. Epidermal growth factor receptor ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse.
MIT Department
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology)
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DOI of Published Version
https://doi.org/10.1073/pnas.2515009122
