Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers
(2025) Cancer Letters — Vol. 613, n° 1, p. 217512 [1-14] (2025)
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Richiardone, Elena 
- Abstract
- (en) 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.
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Citations
Richiardone, E., Giolito, M. V., Al Roumi, R., Ambroise, J., Boidot, R., Drotleff, B., Ghesquière, B., Lupo, B., Trusolino, L., Bardelli, A., Arena, S., Feron, O., & Corbet, C. (2025). Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers. Cancer Letters, 613(1), 217512 [1-14]. https://doi.org/10.1016/j.canlet.2025.217512 (Original work published 2025)