TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer

Jiahui Xu; Xiaoli Yang; Qiaodan Deng; Cong Yang; Dong Wang; Guojuan Jiang; Xiaohong Yao; Xueyan He; Jiajun Ding; Jiankun Qiang; Juchuanli Tu; Rui Zhang; Qun-Ying Lei; Zhi-Min Shao; Xiuwu Bian; Ronggui Hu; Lixing Zhang; Suling Liu

doi:10.1038/s41467-021-24703-7

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.

Authors

Jiahui Xu¹, Xiaoli Yang¹, Qiaodan Deng¹, Cong Yang², Dong Wang³, Guojuan Jiang¹, Xiaohong Yao⁴, Xueyan He¹, Jiajun Ding¹, Jiankun Qiang¹, Juchuanli Tu¹, Rui Zhang¹, Qun-Ying Lei¹, Zhi-Min Shao¹, Xiuwu Bian⁵, Ronggui Hu⁶, Lixing Zhang⁷, Suling Liu⁸

Affiliations

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].

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Biomarkers, Tumor / antagonists & inhibitors
Biomarkers, Tumor / metabolism*
Breast / pathology
Breast / surgery
Carcinogenesis / drug effects
Carcinogenesis / pathology
Cell Line, Tumor
Cell Self Renewal / drug effects
Female
Humans
Mastectomy
Mice
Microfilament Proteins / antagonists & inhibitors
Microfilament Proteins / metabolism*
Middle Aged
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / pathology*
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / pathology*
Receptors, Cell Surface / antagonists & inhibitors
Receptors, Cell Surface / metabolism*
Triple Negative Breast Neoplasms / blood supply
Triple Negative Breast Neoplasms / pathology*
Triple Negative Breast Neoplasms / therapy
Xenograft Model Antitumor Assays

Substances

ANTXR1 protein, human
Antineoplastic Agents
Biomarkers, Tumor
Microfilament Proteins
Receptors, Cell Surface