2. Academic Validation
  3. Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources

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

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. olivier.feron@uclouvain.be.
  • 8 Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium. olivier.feron@uclouvain.be.
  • # 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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