Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, largely due to metastasis and therapeutic resistance. However, the molecular mechanisms driving these processes are still not fully understood.
A recent study published in Genes & Diseases by researchers from Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan University has identified microfibril-associated protein 2 (MFAP2) as a pivotal regulator of epithelial-to-mesenchymal transition (EMT), which fuels both metastasis and chemoresistance in CRC.
Through integrated transcriptomic, proteomic, and molecular analyses, the team demonstrated that MFAP2 expression is markedly elevated in colorectal tumors, particularly in the aggressive CMS4 molecular subtype. Knockdown of MFAP2 significantly inhibited CRC cell proliferation, migration, and invasion, while enhancing sensitivity to standard first-line chemotherapies—5-fluorouracil, irinotecan, and oxaliplatin.
Mechanistic studies revealed that MFAP2 promotes EMT via activation of the EGFR–AKT–STAT3 signaling pathway, thereby fostering tumor progression and drug resistance. Silencing MFAP2 reversed EMT markers—upregulating E-cadherin and downregulating N-cadherin, vimentin, and Snail—suggesting that MFAP2 suppression can reprogram malignant cells toward a less invasive phenotype.
Moreover, clinical data showed that MFAP2 expression positively correlates with tumor stromal scores and inversely with tumor purity, implying a critical role in remodeling the tumor microenvironment. Notably, MFAP2 co-expressed strongly with biglycan (BGN) and thrombospondin 2 (THBS2)—two EMT regulators—suggesting synergistic effects in driving CRC metastasis.
To explore its therapeutic potential, the researchers performed virtual screening and molecular docking of over 10,000 compounds against MFAP2. Among these, (R,S)-ivosidenib, an FDA-approved drug for IDH1-mutant cancers, demonstrated effective MFAP2 binding and significantly impaired CRC cell migration in vitro.
In conclusion, this study identifies MFAP2 as a central regulator of EMT, metastasis, and chemotherapy resistance in colorectal cancer. These findings position MFAP2 as both a prognostic biomarker and a therapeutic target, offering new mechanistic insights and potential strategies for precision treatment—particularly for patients with the CMS4 subtype.
Reference
MFAP2 promotes metastasis and drug resistance by regulating epithelial-to-mesenchymal transition through EGFR signaling pathway in colorectal cancer cells
Journal
Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101800
Funding Information:
- The grant for outstanding talent from abroad by Chinese Academic of Science and Startup Support Funding (No. E0241211H1)
- State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, the Chinese Academy of Sciences, China (No. Y8677211K1, Y8690211Z1)
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