ArticleBMC cancer2025
Methylmalonic acid modulates neutrophil function to promote tumor progression in colorectal cancer.
Article in BMC cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundColorectal cancer (CRC) remains a leading cause of cancer-related mortality, with its progression driven by metabolic reprogramming and an immunosuppressive microenvironment. Methylmalonic acid (MMA), a metabolic byproduct accumulated in CRC, participates in modulating neutrophil function through mechanisms that remain poorly defined.
methodsWe integrated metabolomics, bioinformatics, and multi-omics analyses with in vitro and in vivo experiments. The effects of MMA on neutrophil polarization, proliferation, and invasion were assessed using HL-60-induced and human-derived neutrophils, along with colorectal cancer cell lines (HCT116 and HT29). Functional assays included ELISA, immunofluorescence, EdU proliferation, and invasion assays, while xenograft models assessed tumor growth. Multi-omics interrogation of TCGA, GEO, and CPTAC datasets identified MMA-associated genes and pathways, with hub gene analysis pinpointing key regulators. Plasma MMA levels were quantified in CRC patients via LC–MS/MS, and tumor CXCL8 expression was examined by immunofluorescence. Serum vitamin B12 levels were measured by chemiluminescence immunoassay.
resultsMMA induced dose-dependent N2 neutrophil polarization, evidenced by elevated IL-10, TGF-β, MPO secretion, and CD206 expression, alongside reduced iNOS. MMA-conditioned neutrophils enhanced CRC proliferation and invasion in vitro and promoted tumor growth in xenograft models. Multi-omics analysis revealed 50 MMA-associated differentially expressed genes enriched in SMAD signaling, fatty acid metabolism, and mitochondrial pathways, with CXCL8 emerging as a central hub. Mechanistically, MMA upregulated CXCL8 while suppressing p53 and activating TLR4, thereby driving N2 polarization; CXCL8 silencing abrogated these effects. Clinically, CRC patients exhibited elevated plasma MMA and tumor-specific CXCL8 overexpression, without significant alterations in vitamin B12 status.
conclusionsMMA functions as a metabolic driver of CRC progression, likely by promoting CXCL8-mediated N2 neutrophil polarization through the p53/TLR4 axis. Elevated plasma MMA and tumor CXCL8 expression from CRC patients highlight their potential as biomarkers and therapeutic targets, providing important insights for clinical diagnosis and treatment.
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