Furthermore, we show that human TSPAN6 acts as a tumor suppressor in a mouse orthotopic model of pancreatic cancer, and that full body as well as tissue specific knockout of Tspan6 in mice enhances lung cancer driven by activated Kras. Mechanistically, TSPAN6 binds to the EGFR and suppresses EGFR-RAS-ERK signaling and promotes an epithelial cell morphology in vitro and in vivo. Here, TSPAN6 is linked to neoplasm.