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

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

doi:10.1038/s41467-021-24703-7

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.

Highlights

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC)
We identified genes involved in the regulation of neovasculogenesis in Breast cancer (BC) by analyzing the genetic profiles of seven tumor tissue samples from TNBC patients and the corresponding adjacent non-cancerous tissues, which were overlapped with two angiogenic gene clusters
tumor endothelial marker 8 (TEM8) was widely expressed in breast tumors, and high expression levels of TEM8 were detected in the stroma adjacent to TNBC tumors[38,39]

Summary

Introduction

Especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Analysis of BC cell lines showed high expression of TEM8 in TNBC (Supplementary Fig. 2a). Vessels generated from TNBC tumor cells expressed high levels of TEM8 (Fig. 1b, black arrowheads).

Results

Conclusion