Background Angiogenesis is a fundamental process involved in tumor progression. However, the role of N6-methyladenosine (m⁶A) regulators in tumor angiogenesis remains largely unknown. Here, we elucidate the function and mechanism of the m⁶A reader IGF2 mRNA-binding protein 2 (IGF2BP2) in angiogenesis and tumor progression of colorectal cancer (CRC).

Methods The expression and clinical implications of IGF2BP2 were investigated in multiple CRC cohorts. Intestine-specific Igf2bp2 knock-in mice were generated. The biological function of IGF2BP2 was investigated in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), RIP-seq, Ribo-seq, and RNA-seq were used to identify IGF2BP2 direct targets. Vesicle-like nanoparticles (VNPs)-encapsulated IGF2BP2-siRNA were constructed to target IGF2BP2 in vivo.

Results Combining scRNA-seq from 15 paired primary and metastatic CRC (mCRC) samples and RNA-seq datasets (n=517), we identified that IGF2BP2 mRNA was markedly higher in mCRC than in primary tumors (P<0.0001). Expression levels of IGF2BP2 mRNA and protein were increased in primary tumor compared with adjacent normal tissues. High expression of IGF2BP2 was significantly correlated with tumor angiogenesis (P < 0.01) and poor survival in CRC. In vitro and in vivo functional assays showed that IGF2BP2 promoted angiogenesis, and facilitated colorectal tumorigenesis and metastasis. Mechanistically, integrative multiomics analysis identified CEMIP as a key downstream target of IGF2BP2. IGF2BP2 directly recognized and bound to m⁶A sites on CEMIP mRNA, and enhanced CEMIP mRNA stability. Subsequently, intracellular CEMIP promoted tumor growth and invasion, while secreted CEMIP from cancer cells promoted tumor angiogenesis by recognizing the cell surface receptor GRP78 on endothelial cells to activate the PI3K-AKT pathway. In the azoxymethane-induced CRC model, intestine-specific Igf2bp2 knock-in mice exhibited increased angiogenesis and tumorigenesis compared to wild-type mice (P=0.01). Importantly, inhibiting IGF2BP2 with small-molecule compounds (CWI1-2) or VNPs-siIGF2BP2 potentiated the efficacy of antiangiogenic drugs in CRC xenograft tumors.

Conclusions Our study identifies a novel oncogenic epitranscriptome axis of IGF2BP2-m⁶A-CEMIP, which regulates CRC angiogenesis and progression. Targeting IGF2BP2 is a promising strategy for synergizing the efficacy of anti-angiogenic therapy in CRC.