DAB2IP Is a Bifunctional Tumor Suppressor That Regulates Wild-Type RAS and Inflammatory Cascades in KRAS Mutant Colon
Abigail L Miller1,2, Naiara Perurena1,2, Alycia Gardner1,2
1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Abstract:
The DAB2IP tumor suppressor encodes a RAS GTPase-activating protein. 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 colorectal cancers. In this setting, DAB2IP loss promoted tumor development by activating wild-type H- and N-RAS 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 protumorigenic 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.
Significance:
DAB2IP is lost in early-stage tumors, which amplifies RAS signaling, triggers inflammatory mediators, and recruits macrophages in KRAS-mutant colon cancers.
Insights
Loss of the DAB2IP tumor suppressor amplifies RAS signaling and inflammation in colorectal cancers. This promotes tumor development and macrophage recruitment, offering new therapeutic targets for KRAS-mutant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- DAB2IP (Disabled-2 Interacting Protein) functions as a RAS GTPase-activating protein.
- DAB2IP loss or mutation is observed in tumor types lacking RAS mutations.
- Its role in RAS-mutant cancers, particularly colorectal cancer, remains less understood.
Purpose of the Study:
- To investigate the role of DAB2IP in colorectal cancers with KRAS and BRAF mutations.
- To elucidate the mechanisms by which DAB2IP loss impacts RAS signaling and tumor microenvironment.
- To identify potential therapeutic strategies targeting DAB2IP-deficient colorectal tumors.
Main Methods:
- Analysis of DAB2IP mutation and silencing in colorectal cancer datasets.
- In vivo studies to assess the impact of DAB2IP loss on RAS activation, inflammation, and macrophage recruitment.
- Pharmacological inhibition of inflammatory pathways (JAK/TBK1) and macrophage depletion.
Main Results:
- DAB2IP is frequently mutated or silenced in KRAS/BRAF mutant colorectal cancers.
- DAB2IP loss activates wild-type H- and N-RAS, enhancing RAS effector pathways in KRAS-mutant tumors.
- DAB2IP deficiency triggers inflammatory mediator production and protumorigenic macrophage infiltration.
- Inhibition of inflammation or macrophage depletion suppressed tumor growth in vivo.
- DAB2IP loss occurs early in tumor development and correlates with inflammatory signatures in human tumors.
Conclusions:
- DAB2IP loss is a common mechanism amplifying RAS signaling and inflammation in colorectal cancer.
- DAB2IP restrains RAS pathway activation and inflammatory cascades in the colon.
- Targeting inflammatory pathways or macrophages may be effective in treating DAB2IP-deficient colorectal cancers.
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