TSPAN6 is a suppressor of Ras-driven cancer

Abstract

Oncogenic mutations in the small GTPase RAS contribute to ~30% of human cancers. In a Drosophila genetic screen, we identified novel and evolutionary conserved cancer genes that affect Ras-driven tumorigenesis and metastasis in Drosophila including confirmation of the tetraspanin Tsp29Fb. However, it was not known whether the mammalian Tsp29Fb orthologue, TSPAN6, has any role in RAS-driven human epithelial tumors. Here we show that TSPAN6 suppressed tumor growth and metastatic dissemination of human RAS activating mutant pancreatic cancer xenografts. Whole-body knockout as well as tumor cell autonomous inactivation using floxed alleles of Tspan6 in mice enhanced KrasG12D-driven lung tumor initiation and malignant progression. Mechanistically, TSPAN6 binds to the EGFR and blocks EGFR-induced RAS activation. Moreover, we show that inactivation of TSPAN6 induces an epithelial-to-mesenchymal transition and inhibits cell migration in vitro and in vivo. Finally, low TSPAN6 expression correlates with poor prognosis of patients with lung and pancreatic cancers with mesenchymal morphology. Our results uncover TSPAN6 as a novel tumor suppressor receptor that controls epithelial cell identify and restrains RAS-driven epithelial cancer.

Identifying Tumor-Associated Genes from Bilayer Networks of DNA Methylation Sites and RNAs

“…We identified Cg19858017 for KIRC, corresponding to the gene CLSTN1 , which can be used as a biomarker for a variety of cancers [ 67 , 68 ]. Finally, the most critical node in the BLCA network was Cg01473187, corresponding to the gene TSPAN6 , which is a suppressor of Ras-driven cancer [ 69 ]. In summary, all the genes corresponding to the hub nodes identified were closely associated with tumors according to the two centrality measures.…”

TSPAN6 reinforces the malignant progression of glioblastoma via interacting with CDK5RAP3 and regulating STAT3 signaling pathway

“…For instance, TSPAN6 is increased in AD brains and is a pivotal protein determining exosome release 35 . TSPANs show conflicting results on expression in different tumor types, it has been reported that TSPAN6 acts as a tumor suppressor gene in the development of colorectal and pancreatic cancer 9 , 10 . So far, the function of TSPAN6 in glioblastoma development has not been elucidated.…”

“…Transmembrane TSPANs regulate tumor microenvironment (TME) and act a vital role in tumor progression, they can either enhance or inhibit tumor metastasis depend on the multimolecular transmembrane complex 8 . Tetraspanin-6 (TSPAN6) is a member of TSPANs and acts as an inhibitor of Ras-driven pancreatic cancer, it interacts with the epidermal growth factor receptor (EGFR) and impedes the activation of RAS induced by EGFR 9 . Meanwhile, TSPAN6 acts as a tumor suppressor gene in the progression of colorectal cancer 10 .…”

The versatile roles of testrapanins in cancer from intracellular signaling to cell–cell communication: cell membrane proteins without ligands

“…Furthermore, CD151–α3β1/α6β4 integrin complexes can recruit and activate small G proteins (RAS, RAC1, and CDC42) in melanoma cell lines [ 8 ]. Other partners of TSPANs include growth factor receptors (EGFR [ 9 ], mtTGF-β [ 10 ]), transporters (ASCT2 [ 11 ], FATP1 [ 12 ], MDR1 [ 13 ]), membrane-linked kinases (BTRC [ 14 ], SOCSS3 [ 15 ], ATXN3 [ 16 ]), other transmembrane proteins (ADAM10 [ 17 ], CD44 [ 18 ], p120 [ 19 ]) or some nonproteins such as cholesterol [ 20 ]. For example, TSPAN6 could bind with EGFR and inhibit its downstream KRAS-ERK1/2 signaling to suppress KRAS-driven cancer initiation and metastasis [ 20 ](Fig.…”

“…Whole-body knockout as well as tumor cell autonomous inactivation using floxed alleles of TSPAN6 in mice enhanced Kras G12D -driven lung tumor initiation and malignant progression. Similar to the function in lung cancer cells, TSPAN6 binds to the EGFR and blocks EGFR-induced RAS activation, thus inhibiting EMT process and cell migration [ 20 ]. The proliferation, migration and invasion of human gastric cancer SGC7901 cells were significantly inhibited by overexpression of TSPAN9, which is mediated by the inhibition of ERK1/2 signaling and MMP-9 expression [ 70 ].…”