Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources

  • Nat Commun. 2024 Nov 21;15(1):10107. doi: 10.1038/s41467-024-54435-3.
Katarzyna Głowacka  #  1 ,  Sébastien Ibanez  #  1 ,  Ophélie Renoult  1 ,  Perrine Vermonden  2 ,  Maria Virginia Giolito  1 ,  Kübra Özkan  1 ,  Charline Degavre  1 ,  Léo Aubert  1 ,  Céline Guilbaud  1 ,  Florine Laloux-Morris  1 ,  Elena Richiardone  1 ,  Jérôme Ambroise  3 ,  Caroline Bouzin  4 ,  Davide Brusa  5 ,  Jonas Dehairs  6 ,  Johan Swinnen  6 ,  Cyril Corbet  1 ,  Yvan Larondelle  2 ,  Olivier Feron  7  8
Affiliations
  • 1. Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium.
  • 2. Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium.
  • 3. Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium.
  • 4. Imaging Platform 2IP, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium.
  • 5. CytoFlux-Flow Cytometry and Cell Sorting Platform, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium.
  • 6. Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • 7. Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium. [email protected].
  • 8. Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium. [email protected].
  • # Contributed equally.
PMID: 39572570 DOI: 10.1038/s41467-024-54435-3
Abstract

Cancer cells in acidic tumor regions are aggressive and a key therapeutic target, but distinguishing between acid-exposed and hypoxic cells is challenging. Here, we use Carbonic Anhydrase 9 (CA9) antibodies to MARK acidic areas in both hypoxic and respiring tumor areas, along with an HRE-GFP reporter for hypoxia, to isolate distinct cell populations from 3D tumor spheroids. Transcriptomic analysis of CA9-positive, hypoxia-negative cells highlights enriched fatty acid desaturase activity. Inhibiting or silencing stearoyl-CoA desaturase-1 (SCD1) induces Ferroptosis in CA9-positive acidic Cancer cells and delays mouse tumor growth, an effect enhanced by omega-3 fatty acid supplementation. Using acid-exposed Cancer cells and patient-derived tumor organoids, we show that SCD1 inhibition increases acidic Cancer cell reliance on external mono-unsaturated fatty acids, depriving hypoxic cells of essential resources. This bystander effect provides unbiased evidence for a lack of full overlap between hypoxic and acidic tumor compartments, highlighting a rationale for targeting desaturase activity in Cancer.

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