Tumor Endothelial Marker 8 Promotes Proliferation and Metastasis via the Wnt/β-Catenin Signaling Pathway in Lung Adenocarcinoma

Tumor endothelial marker 8 (TEM8), also known as ANTXR1, was highly expressed in cancers, and was identified as a biomarker for early diagnosis and prognosis in some cancers. However, the clinical role and molecular mechanisms of TEM8 in lung adenocarcinoma (LUAD) are still unclear. The present study aimed to explore its clinical value and the molecular mechanisms of TEM8 underlying the progression of LUAD. Our study found the elevation of TEM8 in LUAD cell lines and tissues. What’s more, we observed that the TEM8 expression level was associated with tumor size, primary tumor, and AJCC stage, and LUAD patients with high TEM8 expression usually have a poor prognosis. Then, we conducted a series of experiments by the strategy of loss-of-function and gain-of-function, and our results suggested that the knockdown of TEM8 suppressed proliferation, migration, and invasion and induced apoptosis in LUAD whereas overexpression of TEM8 had the opposite effect. Molecular mechanistic investigation showed that TEM8 exerted its promoting effects mainly through activating the Wnt/β-catenin signaling pathway. In short, our findings suggested that TEM8 played a crucial role in the progression of LUAD by activating the Wnt/β-catenin signaling pathway and could serve as a potential therapeutic target for LUAD.

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

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.

GENE-51. ROLE OF TUMOR ENDOTHELIAL MARKER 8 (TEM8) IN PRIMARY AND RECURRENT GLIOBLASTOMA.

Glioblastoma (GBM) is the most common primary malignant tumor of the adult central nervous system. It is highly invasive and almost inevitably recurs; leading to a median survival of 15 months. The recurrent tumor in most cases is radiotherapy and chemotherapy-resistant, making them quite challenging to treat. Several studies have elucidated key driver genes and molecular pathways involved in Gliomagenesis, but genes/pathways that might be involved in aiding relapse are not well elucidated. Interestingly, chemotherapy with Temozolomide and γ-irradiation have been documented to alter the DNA methylome of cells in vitro. A probable hypothesis could be that following surgical resection, therapy alters the epigenome of residual cancer cells giving rise to aggressively resistant recurrent tumors. To examine this possibility, 24 GBM biopsies (11 primary and 13 recurrent GBMs) were subjected to Methylation Bead Array to assess differential methylation of genes in recurrent GBM compared to primary tumors. This was correlated with RNA-seq data for recurrent tumors in TCGA database. A total of 1751 differentially methylated regions (DMRs) were identified, among which 205 differentially methylated genes (74 hypomethylated and 131 hypermethylated) were found to correlate with methylation and RNA-sequencing data of recurrent tumors in TCGA. Among these genes, ANTXR1/TEM8 (Tumor Endothelial Marker 8) was found to be overexpressed in recurrent tumors compared to primary tumors at both transcript and protein levels using RT-PCR and immunohistochemistry, respectively. When overexpressed in Glioma cell lines, TEM8 was found to upregulate phospho-GSK3β, phospho-AKT and lead to β-catenin translocation to the nucleus resulting in activation of Wnt signaling pathway. TEM8 overexpressing cells showed mild enhancement in proliferation and resistance to Temozolomide, Cisplatin and 5-fluoroUracil. Stem cells markers like Oct4 and Nanog are also upregulated. In conclusion, TEM8 may be involved in GBM recurrence and may have a role in conferring chemo- and radioresistance.

Converging physiological roles of the anthrax toxin receptors

The anthrax toxin receptors—capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8)—were identified almost 20 years ago, although few studies have moved beyond their roles as receptors for the anthrax toxins to address their physiological functions. In the last few years, insight into their endogenous roles has come from two rare diseases: hyaline fibromatosis syndrome, caused by mutations in CMG2, and growth retardation, alopecia, pseudo-anodontia, and optic atrophy (GAPO) syndrome, caused by loss-of-function mutations in TEM8. Although CMG2 and TEM8 are highly homologous at the protein level, the difference in disease symptoms points to variations in the physiological roles of the two anthrax receptors. Here, we focus on the similarities between these receptors in their ability to regulate extracellular matrix homeostasis, angiogenesis, cell migration, and skin elasticity. In this way, we shed light on how mutations in these two related proteins cause such seemingly different diseases and we highlight the existing knowledge gaps that could form the focus of future studies.