A recent study published in Engineering has shed light on a novel therapeutic target for improving anti-angiogenic treatment in colorectal cancer (CRC). The research, conducted by an international team of scientists from institutions including Sun Yat-sen University and The Chinese University of Hong Kong, identified the RNA N⁶-methyladenosine (m⁶A) reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a key regulator of angiogenesis in CRC. The findings suggest that targeting IGF2BP2 could enhance the efficacy of existing anti-angiogenic therapies.

Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide, with over 20% of cases diagnosed at an advanced stage, resulting in a low five-year survival rate of 14%. Angiogenesis, the formation of new blood vessels, is a critical driver of tumor progression, recurrence, and metastasis. Tumor cells release angiogenic signals that stimulate endothelial cell proliferation and migration, leading to the formation of immature and dysfunctional vessels. Anti-angiogenic drugs, such as bevacizumab and regorafenib, are currently used in clinical management, but their efficacy is often limited due to rapid drug resistance.

The study began by analyzing the expression profiles of m⁶A regulators in CRC samples from multiple datasets, revealing that IGF2BP2 was consistently upregulated in CRC tissues with high angiogenesis scores. Further investigation using immunohistochemistry and single-cell RNA sequencing confirmed a strong correlation between IGF2BP2 expression and angiogenesis in CRC tissues. The researchers demonstrated that IGF2BP2 expression was associated with poor prognosis in CRC patients, making it a potential biomarker for disease progression.

To explore the functional role of IGF2BP2 in CRC, the researchers conducted in vitro and in vivo experiments. They found that IGF2BP2 knockdown in CRC cells significantly reduced the pro-angiogenic capacity of these cells, as evidenced by decreased tube formation and sprouting in endothelial cells. Conversely, overexpression of IGF2BP2 enhanced angiogenesis and vascular leakiness. In animal models, intestine-specific IGF2BP2 knock-in mice exhibited accelerated CRC development through enhanced angiogenesis, while IGF2BP2 knockout mice showed inhibited tumor growth and normalized tumor vasculature.

Mechanistically, the study revealed that IGF2BP2 binds to m⁶A-modified cell migration inducing and hyaluronan binding protein (CEMIP) mRNA, stabilizing it and increasing its secretion. Secreted CEMIP interacts with membrane glucose-regulated protein 78 (GRP78) on endothelial cells, activating pro-angiogenic signaling pathways. This interaction promotes angiogenesis and vascular abnormalities, facilitating tumor progression and metastasis.

Importantly, the researchers demonstrated that targeting IGF2BP2 through genetic ablation, lipid nanoparticle (LNP)-encapsulated small interfering RNA, or a chemical inhibitor (CWI1-2) synergized with anti-angiogenic drugs to suppress tumor growth in multiple CRC models. This suggests that IGF2BP2 could be a promising therapeutic target for enhancing the effectiveness of anti-angiogenic therapies in CRC.

The study’s findings highlight the importance of IGF2BP2 in CRC angiogenesis and provide a new direction for improving treatment outcomes. By elucidating the role of IGF2BP2 in promoting angiogenesis through the m⁶A-CEMIP-GRP78 axis, the research offers a potential strategy for overcoming resistance to anti-angiogenic therapies. Future work may focus on further exploring the therapeutic potential of IGF2BP2 targeting in clinical settings, potentially leading to more effective treatments for colorectal cancer patients.

The paper “Targeting IGF2BP2–CEMIP Boosts Antiangiogenic Therapy in Colorectal Cancer in Mice,” is authored by Weikang Chen, Haojie Bai, Yani Huo, Yifan Wu, Wei Kang, Dong Zhang, Yongxin Zhang, Shiyan Wang, Lixia Xu, Chi Chun Wong, Ka Fai To, Xiaoxing Li, Jun Yu. Full text of the open access paper: https://doi.org/10.1016/j.eng.2025.06.035. For more information about Engineering, visit the website at https://www.sciencedirect.com/journal/engineering.