Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.

Fiche publication

Date publication

février 2025

Journal

Cancer letters

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BOIDOT Romain

Tous les auteurs :
Richiardone E, Giolito MV, Al Roumi R, Ambroise J, Boidot R, Drotleff B, Ghesquière B, Lupo B, Trusolino L, Bardelli A, Arena S, Feron O, Corbet C

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/39900217

Résumé

Colorectal cancer (CRC) represents a prototypical example of a cancer type for which inter- and intra-tumor heterogeneities remain major challenges for the clinical management of patients. Besides genotype-mediated phenotypic alterations, tumor microenvironment (TME) conditions are increasingly recognized to promote intrinsic diversity and phenotypic plasticity and sustain disease progression. In particular, acidosis is a common hallmark of solid tumors, including CRC, and it is known to induce aggressive cancer cell phenotypes. In this study, we report that long-term adaptation to acidic pH conditions is associated with common metabolic alterations, including a glycolysis-to-respiration switch and a higher reliance on the activity of phosphoglycerate dehydrogenase (PHGDH), in CRC cells initially displaying molecularly heterogeneous backgrounds. Pharmacological inhibition of PHGDH activity or mitochondrial respiration induces greater growth-inhibitory effects in acidosis-exposed CRC cells in 2D and 3D culture conditions, and in patient-derived CRC organoids. These data pave the way for drugs targeting the acidic tumor compartment as a "one-size-fits-all" therapeutic approach to delay CRC progression.