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

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

  • Cancer Lett. 2025 Mar 31:613:217512. doi: 10.1016/j.canlet.2025.217512.
Elena Richiardone 1,  Maria Virginia Giolito 1,  Rim Al Roumi 1,  Jérôme Ambroise 2,  Romain Boidot 3,  Bernhard Drotleff 4,  Bart Ghesquière 5,  Barbara Lupo 6,  Livio Trusolino 6,  Alberto Bardelli 7,  Sabrina Arena 6,  Olivier Feron 8,  Cyril Corbet 9
Affiliations

Affiliations

  • 1 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium.
  • 2 Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 54, B-1200, Brussels, Belgium.
  • 3 Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges-François Leclerc Cancer Center-UNICANCER, 21079, Dijon, France.
  • 4 Metabolomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
  • 5 Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Metabolomics Core Facility Leuven, Center for Cancer Biology, VIB, Leuven, Belgium.
  • 6 Department of Oncology, University of Torino, Candiolo (TO), Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo (TO), Italy.
  • 7 Department of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy; IFOM ETS, The AIRC Institute of Molecular Oncology, 20139, Milan, Italy.
  • 8 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium; WEL Research Institute, Avenue Pasteur 6, B-1300, Wavre, Belgium.
  • 9 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium; WEL Research Institute, Avenue Pasteur 6, B-1300, Wavre, Belgium. Electronic address: cyril.corbet@uclouvain.be.
PMID: 39900217 DOI: 10.1016/j.canlet.2025.217512
Abstract

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.

Keywords

Acidosis; Colon cancer; Metabolism; Microenvironment; Mitochondrial respiration; PHGDH.

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