TSPAN6 is a suppressor of Ras-driven cancer

Patrick O Humbert,Andrew Farrell,Astrid Hagelkruys,Ivona Kozieradzki,Blanka Pranjic,Josef M Penninger,Helena E Richardson,Tamara Zoranovic Pryjda,Shane J F Cronin,Ricardo De Matos Simoes,Thomas F Meyer,Kohei Fujikura,Rezaul Karim,G Gregory Neely

doi:10.1038/s41388-022-02223-y

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.

Highlights

INTRODUCTION The3 RAS proteins (H-RAS, N-RAS, and K-RAS) are small GTPase binary molecular switches, that switch between active (GTP bound) and inactive (GDP bound) states [1]
We examined the cooperation of TSPAN6 knockdown with H-RASV12 in 3D MCF10A cultures, where SCRIB or DLG1 knockdown have been shown to cooperate with H-RASV12 in inducing an invasive phenotype [11]
Whereas low or high expression of H-RASV12 in cells resulted in a small number of invasive spikes in the acini, we found that knockdown of TSPAN6, greatly increased the number of invasive spikes in acini, similar to the knockdown of SCRIB or DLG1 (Fig. 1b and Supplementary Fig. 1) [11]

Summary

Introduction

INTRODUCTION The3 RAS proteins (H-RAS, N-RAS, and K-RAS) are small GTPase binary molecular switches, that switch between active (GTP bound) and inactive (GDP bound) states [1]. Gain of function mutations of RAS, such as RASV12, that increase the levels of the GTP-bound version of the protein were first observed in cancers approximately 40 years ago [4]. Activating mutation in RAS leads to a cascade of molecular events affecting cell proliferation, cell survival, and, lead to carcinogenesis [5, 6]. Activating RAS mutations are common, this event is rarely sufficient to promote tumorigenesis, as it promotes cellular senescence [7,8,9,10]. Additional mutations or silencing of tumor suppressors is frequently needed to promote tumorigenesis and metastasis together with activation of the RAS signaling pathway [11,12,13]

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Results

Conclusion