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.
JMP was supported by IMBA, ERC Advanced Investigator grant, an Innovator Award from Era of Hope, the T. von Zastrow foundation, and a Canada 150 Chair in Functional Genetics. TZP was supported by a Marie Curie Excellence grant. RK was supported by Infla-Care and Infect-ERA grants. RdMS was supported by a grant from Invest NI RD0412515. AF was supported from funds from the Cancer Council Victoria (Australia) to HER, POH, and JMP. HER and POH were supported by fellowships from the National Health & Medical Research Council (NHMRC), Australia, and by funds from La Trobe University.