Inflammation awakens dormant cancer cells by modulating the epithelial-mesenchymal phenotypic state

• 成果类型: Article
• 署名作者: Zhang, Jingwei; Zhang, Jingwen; Han, Longfei; Wu, Shiyi; Li, Jie; Eaton, Elinor Ng; Yuan, Bingbing; Reinhardt, Ferenc; Li, Hao; Strasser, Patrick C.; Das, Sunny; Donahera, Joana Liu; Khalila, Md Imtiaz; Jiang, Haiping; Deuschel, Alexander; Lin, Danni; Sebastiany, Carolin; Maranga, Mariana; Shubitidze, Salome; Liu, Xiaofei; Lambert, Arthur W.; Zhang, Yun; Liu, Yana; Sui, Lufei; Elmiligy, Sarah; Pozza, Umberto; Gunsay, Rauf; Mishra, Ranjan; Velarde, Jose; Iyer, Sonia; Henra, Whitney S.; Weiskopf, Kipp; Fen, Guihai; Oni, Tobiloba E.; Watnick, Randolph S.; Li, Xin; Weinberg, Robert A.
• 署名单位: Massachusetts Institute of Technology (MIT); Whitehead Institute; Chinese Academy of Sciences; Institute of Zoology, CAS; Chinese Academy of Sciences; Beijing Institute for Stem Cell & Regenerative Medicine; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Nankai University; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Cancer Institute & Hospital - CAMS; Chinese Academy of Medical Sciences - Peking Union Medical College; Cancer Institute & Hospital - CAMS; Peking Union Medical College; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of Bergen; University of Bergen; Haukeland University Hospital; Massachusetts Institute of Technology (MIT)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9855
• DOI: 10.1073/pnas.2515009122
• 发表日期: 2025-09-09
• 关键词: breast-cancer; metastatic colonization; emt; macrophages; alpha

摘要

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 peutic 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 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.