Targeting IGF2BP2–CEMIP Boosts Antiangiogenic Therapy in Colorectal Cancer in Mice

Abstract

Angiogenesis is essential for supporting tumor progression and metastasis. However, the potential role of the epitranscriptome in regulating angiogenesis remains unclear. Here, we identify the RNA N⁶-methyladenosine (m⁶A) reader insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding protein 2 (IGF2BP2) as the top enriched m⁶A regulator in hypervascular colorectal cancer (CRC), with its expression correlating with poor prognosis. Knockdown of IGF2BP2 in CRC cells suppressed their ability to promote pro-angiogenic phenotypes in endothelial cells in vitro, as well as vascular abnormalization, tumor progression, and metastasis in vivo. Supporting these findings, intestine-specific Igf2bp2 knock-in mice exhibited accelerated azoxymethane (AOM) plus dextran sulfate sodium (DSS)-induced CRC through enhanced angiogenesis and vascular abnormalities, whereas intestine-specific Igf2bp2 knockout inhibited tumor growth by normalizing tumor vasculature. Mechanistically, IGF2BP2 binds to m⁶A-modified cell migration inducing and hyaluronan binding protein (CEMIP) mRNA and enhanced its stability, leading to increased secretion of CEMIP. Secreted CEMIP interacts with membrane glucose-regulated protein 78 (GRP78) on endothelial cells, activating pro-angiogenic signaling. Importantly, targeting IGF2BP2 through genetic ablation, lipid nanoparticle (LNP)-encapsulated small interfering IGF2BP2, or the chemical inhibitor (CWI1-2) synergized with anti-angiogenic drugs to suppress tumor growth in multiple CRC models. Together, these findings suggest that targeting IGF2BP2 is a promising strategy to enhance the efficacy of anti-angiogenic therapy in CRC.