DAB2IP肿瘤抑制因子编码RAS GTP酶活化蛋白（RASGAP）。因此，DAB2IP已被证实会在通常缺乏RAS突变的肿瘤类型中发生突变或受到压制。然而，在这种情况下，我们报告DAB2IP在绝大多数KRAS和BRAF突变的结直肠癌中发生突变或被选择性地沉默。在这种情况下，DAB2IP的丧失通过激活野生型H-和NRAS蛋白促进了肿瘤的发展，这令人惊讶地需要在KRAS突变的肿瘤中实现强大的RAS效应途径的激活。DAB2IP的丧失还会触发炎症介质的产生和前瘤性巨噬细胞的招募。重要的是，通过耗竭巨噬细胞或使用JAK/TBK1抑制剂抑制细胞因子/炎症介质的表达来抑制肿瘤生长。在人类肿瘤中，DAB2IP在肿瘤早期阶段就已经消失，并且其丧失与巨噬细胞和炎症特征的富集有关。总之，这些发现证明了DAB2IP在结肠中抑制RAS信号通路和炎症级联反应的激活，并且其丧失代表了在结直肠癌中放大这两种关键致癌信号的常见且未被重视的机制。

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.