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

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.

Antibody-drug conjugates: beyond current approvals and potential future strategies

“…Another novel target for ADC development has been TEM8, a transmembrane glycoprotein initially found to be a TEM but more recently also shown to be expressed widely in the tumour stroma across several human tumours [121][122][123]. The TEM8 targeting m825 [124] was developed into an ADC by conjugating it with MMAE via a cleavable linker.…”

Evolving role of seneca valley virus and its biomarker TEM8/ANTXR1 in cancer therapeutics

“…TEM8/ANTXR1 is unique in its association with tumor vessels but not normal blood vessels (Chaudhary et al, 2012). TEM8/ANTXR1 has been described as a marker for pathological, tumor-associated angiogenesis, which promotes tumor growth and may mediate resistance to therapies targeting angiogenesis (Xu et al, 2021).…”

“…Studies have demonstrated that TEM8/ANTXR1 is enriched in triple negative breast cancer (Xu et al, 2021), prostate cancer (Li et al, 2021a), gastric cancer (Li et al, 2021b;Sun et al, 2021), pancreatic cancer (Alcalá et al, 2019), angiosarcoma (Kusaba et al, 2021(Kusaba et al, ), colon cancer (Ł et al, 2021, and non-small cell lung cancer (NSCLC) (Gong et al, 2021). In multiple tumor types, upregulation of TEM8/ ANTXR1 is a negative prognostic indicator (Li et al, 2021a;Ł et al, 2021;Ding et al, 2021).…”

“…In multiple tumor types, upregulation of TEM8/ ANTXR1 is a negative prognostic indicator (Li et al, 2021a;Ł et al, 2021;Ding et al, 2021). In triple negative breast cancer, TEM8/ANTXR1, is marker of vasculogenic mimicry, and is associated with poor outcomes (Fernández-Cortés et al, 2019;Xu et al, 2021). Vasculogenic mimicry is a process where tumor cells organize themselves into structures mimicking endothelial cells with functional tubes that can carry red blood cells.…”

“…However, understanding SVV-001 and the unique tumor microenvironment, represented by upregulation of TEM8/ANTXR1, that it targets, has the potential to provide additional clues about mechanisms of resistance to immunotherapy and chemotherapy in neuroendocrine neoplasms and other cancers. TEM8/ANTXR1 upregulation has been described in a variety of solid tumors types including triple negative breast cancer (Xu et al, 2021), prostate cancer (Li et al, 2021a), gastric cancer (Li et al, 2021b;Sun et al, 2021), pancreatic cancer (Alcalá et al, 2019), angiosarcoma (Kusaba et al, 2021(Kusaba et al, ), colon cancer (Ł et al, 2021, and NSCLC (Gong et al, 2021). Lineage plasticity with a transformation from adenocarcinomas to carcinomas with neuroendocrine differentiation has been described in a variety of solid tumors, including lung and prostate primary tumors (Farrell et al, 2017;Rubin et al, 2020;Ito et al, 2021).…”