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, Zhimin Shao, Xiu‐Wu Bian, Ronggui Hu, Lixing Zhang, Suling Liu
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.