DAB2IP is a bifunctional tumor suppressor that regulates wildtype RAS and inflammatory cascades in KRAS mutant colon cancer.

The DAB2IP tumor suppressor encodes a RAS GTPase-activating protein (RASGAP). Accordingly, DAB2IP has been shown to be mutated or suppressed in tumor types that typically lack RAS mutations. However, here we report that DAB2IP is mutated or selectively silenced in the vast majority of KRAS and BRAF mutant CRCs. In this setting, DAB2IP loss promoted tumor development by activating wild-type H- and NRAS proteins, which was surprisingly required to achieve robust activation of RAS effector pathways in KRAS-mutant tumors. DAB2IP loss also triggered production of inflammatory mediators and the recruitment of pro-tumorigenic macrophages in vivo. Importantly, tumor growth was suppressed by depleting macrophages or inhibiting cytokine/inflammatory mediator expression with a JAK/TBK1 inhibitor. In human tumors DAB2IP was lost at early stages of tumor development, and its depletion was associated with an enrichment of macrophage and inflammatory signatures. Together, these findings demonstrate that DAB2IP restrains the activation of the RAS pathway and inflammatory cascades in the colon and that its loss represents a common and unappreciated mechanism for amplifying these two critical oncogenic signals in colorectal cancer.