Phosphatidylcholine and CHPT1 as Central Drivers of Chemoresistance in Colorectal Cancer: Lipidomic and Functional Insights.

Fiche publication

Date publication

février 2026

Journal

Cells

Auteurs

Membres identifiés du Cancéropôle Est :
Pr DELMAS Dominique , Pr GHIRINGHELLI François , Dr HERMETET François , Dr PAIS DE BARROS Jean-Paul , Dr AIRES Virginie , Dr LIMAGNE Emeric

Tous les auteurs :
Mialhe A, Pais de Barros JP, Hermetet F, Limagne E, Ghiringhelli F, Aires V, Delmas D

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/41827872

Résumé

Chemoresistance remains a major barrier to effective colorectal cancer (CRC) therapy, yet its metabolic underpinnings are poorly defined. Here, we integrate lipidomic profiling, enzymatic analysis, and functional perturbation approaches to elucidate the contribution of phosphatidylcholine (PC) metabolism and its biosynthetic regulator Choline Phosphotransferase 1 (CHPT1) to drug response. Comparative analysis of chemosensitive and chemoresistant CRC cell lines revealed that resistant HT29 cells exhibited significantly higher PC content and altered PC/lysophosphatidylcholine (LPC)ratios relative to sensitive counterparts. Importantly, functional perturbation confirmed causality: CHPT1 overexpression in SW620 cells was sufficient to promote PC accumulation and confer a chemoresistant phenotype. These findings identify CHPT1 as a metabolic gatekeeper of chemoresistance. Consistently, Human Protein Atlas survival analyses further support its clinical relevance, as elevated CHPT1 expression correlates with poor patient outcomes in CRC. Mechanistically, CHPT1-driven PC enrichment may sustain pro-survival signaling, while reducing lysophospholipid-mediated stress pathways. To therapeutically target this vulnerability, we investigated edelfosine (Edel), an alkyl-lysophospholipid that disrupts lipid rafts and inhibits PC biosynthesis upstream of CHPT1. Notably, edelfosine-mediated disruption of the Kennedy pathway enhances chemosensitivity in the resistant CRC model. Collectively, our study identifies CHPT1 and PC metabolism as central determinants of CRC drug response and proposes edelfosine-based metabolic reprogramming as a promising strategy to overcome resistance.