TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer
- Nat Commun. 2021 Jul 20;12(1):4413. doi: 10.1038/s41467-021-24703-7.
- 1. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China.
- 2. School of Medicine, Guizhou University, Guiyang, Guizhou, China.
- 3. WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
- 4. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University); Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
- 5. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University); Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. [email protected].
- 6. State Key Laboratory of Molecular Biology; CAS Center for Excellence in Molecular Cell Science; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. [email protected].
- 7. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
- 8. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast Cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast Cancer cells. ASB10, an Estrogen receptor ERα trans-activated E3 Ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.