Inflammation awakens dormant cancer cells by modulating the epithelial–mesenchymal phenotypic state
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.
Authors
- Tobiloba E. Oni (ORCID: https://orcid.org/0000-0002-6916-3380)
- Shiyi Wu
- Robert A. Weinberg (ORCID: https://orcid.org/0000-0002-0895-3557)
- Ferenc Reinhardt
- Rauf Günsay (ORCID: https://orcid.org/0000-0002-9493-7587)
- Md Imtiaz Khalil (ORCID: https://orcid.org/0000-0003-0345-2101)
- Sunny Das (ORCID: https://orcid.org/0000-0003-1154-3441)
- Sonia Iyer (ORCID: https://orcid.org/0000-0003-3840-5583)
- Longfei Han (ORCID: https://orcid.org/0000-0003-2135-6228)
- Yana Liu (ORCID: https://orcid.org/0000-0002-9101-9772)
- Kipp Weiskopf (ORCID: https://orcid.org/0000-0002-9008-445X)
- Whitney S. Henry (ORCID: https://orcid.org/0000-0002-2059-3996)
- José Velarde (ORCID: https://orcid.org/0000-0001-9001-1923)
- Joana Liu Donaher
- Randolph S. Watnick (ORCID: https://orcid.org/0000-0001-5755-5638)
- Guihai Feng (ORCID: https://orcid.org/0000-0002-8726-1734)
- Sarah Elmiligy
- Danni Lin (ORCID: https://orcid.org/0009-0007-3923-2027)
- Lufei Sui (ORCID: https://orcid.org/0000-0002-7100-7328)
- Haiping Jiang
- Patrick C. Strasser (ORCID: https://orcid.org/0000-0002-7368-3354)
- Arthur W. Lambert (ORCID: https://orcid.org/0000-0002-2989-7961)
- Carolin Sebastiany
- Hao Li (ORCID: https://orcid.org/0000-0002-1135-1944)
- Yun Zhang (ORCID: https://orcid.org/0000-0003-1614-1943)
- Xiaofei Liu (ORCID: https://orcid.org/0000-0001-7524-485X)
- Jingwei Zhang (ORCID: https://orcid.org/0000-0002-4188-2236)
- Jingwen Zhang (ORCID: https://orcid.org/0000-0003-4071-4449)
- Xin Li (ORCID: https://orcid.org/0000-0002-1255-9173)
- Jie Li (ORCID: https://orcid.org/0000-0002-6175-3167)
- Ranjan Mishra
- Bingbing Yuan (ORCID: https://orcid.org/0000-0002-8460-5124)
- Elinor Ng Eaton
- Mariana Maranga
- Alexander Deuschel
- Salomé Shubitidze
- Umberto Pozza
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- California Institute for Regenerative Medicine (US)
- Ludwig Cancer Research (BE)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nankai University (CN)
- Haukeland University Hospital (NO)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- National Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- National Clinical Research (US)
- Allen Institute (US)
- Molecular Oncology (United States) (US)
- Boston Children's Museum (US)
- Whitehead Institute for Biomedical Research (US)
- University of Chinese Academy of Sciences (CN)
- Institute of Zoology (CN)
- University of Bergen (NO)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-09-03
- DOI
- https://doi.org/10.1073/pnas.2515009122
- Citations
- 1
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- U.S. Department of Defense
- Breast Cancer Research Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- Ludwig Institute for Cancer Research
- J. Willard and Alice S. Marriott Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- National Institutes of Health
- Ludwig Center at Harvard
- Institute of Zoology, Chinese Academy of Sciences
- National Key Research and Development Program of China