Inflammation awakens dormant cancer cells by modulating the epithelial–mesenchymal phenotypic state
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (37)
Jingwei Zhang
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter
Jingwen Zhang
Longfei Han
State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences
Shiyi Wu
Whitehead Institute for Biomedical Research
Jie Li
Elinor Ng Eaton
Whitehead Institute for Biomedical Research
Bingbing Yuan
Center of Excellence for Renewable Energy and Storage Technologies (CREST), Division of Physical Science and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia.
Ferenc Reinhardt
Whitehead Institute for Biomedical Research
Hao Li
Patrick C. Strasser
Whitehead Institute for Biomedical Research
Sunny Das
Whitehead Institute for Biomedical Research
Joana Liu Donaher
Whitehead Institute for Biomedical Research
Md Imtiaz Khalil
Whitehead Institute for Biomedical Research
Haiping Jiang
Alexander Deuschel
Whitehead Institute for Biomedical Research
Danni Lin
Carolin Sebastiany
Whitehead Institute for Biomedical Research
Mariana Maranga
Whitehead Institute for Biomedical Research
Salomé Shubitidze
Whitehead Institute for Biomedical Research
Xiaofei Liu
School of Pharmaceutical Sciences
Arthur W. Lambert
Whitehead Institute for Biomedical Research
Yun Zhang
Yana Liu
New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Key Laboratory of Analysis and Testing Technology for Food Safety and Health, College of Chemistry
Lufei Sui
Vascular Biology Program, Boston Children’s Hospital
Sarah Elmiligy
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Umberto Pozza
Whitehead Institute for Biomedical Research
Rauf Günsay
Whitehead Institute for Biomedical Research
Ranjan Mishra
Whitehead Institute for Biomedical Research
Jose Velarde
Whitehead Institute for Biomedical Research
Sonia Iyer
Whitehead Institute for Biomedical Research
Whitney S. Henry
Whitehead Institute for Biomedical Research
Kipp Weiskopf
Whitehead Institute for Biomedical Research
Guihai Feng
State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences
Tobiloba E. Oni
Whitehead Institute for Biomedical Research
Randolph S. Watnick
Vascular Biology Program, Boston Children’s Hospital
Xin Li
Robert A. Weinberg