Role of RRAS2 as an oncogenic driver
Centro de Investigación del Cáncer (CIC-IBMCC)
R-RAS2 is a small GTPase with high structural proximity to classical RAS proteins. RRAS2 gain-of-function mutations have been identified at low frequency in recent PanCancer studies. However, the cancer driver and pathobiological roles of this GTPase remain poorly characterized. To tackle those issues, we have used in vitro and in vivo models. Firstly, we used an in vitro approach to characterize the oncogenic potential of R-RAS2 mutations. Secondly, we used a Cre-regulated knock-in model to express a gain-of-function R-Ras2 mutant (Q72L) either systemically or in an ovary-specific manner in mice. Using this method, we have found that the expression of this gain-of-function mutant triggers follicular atresia-induced infertility and, subsequently, ovarian cystadenomas at high penetrance. Lastly, elimination of endogenous R-RAS2Q72L, but not of the wild-type counterpart, impairs the tumorigenic potential of these cells both in culture and xenotransplants. This is connected to reduced levels of MEK-ERK and PI3K-AKT signaling, polysomal translation rates, and basic metabolic activities. Together, these data indicate that RRAS2Q72L mutations do play cancer driver roles in ovarian tumors.