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

Katarzyna Głowacka, Sébastien Ibanez, Ophélie Renoult, Perrine Vermonden, Maria Virginia Giolito, Kübra Özkan, Charline Degavre, Léo Aubert, Céline Guilbaud, Florine Laloux-Morris, Elena Richiardone, Jérôme Ambroise, Caroline Bouzin, Davide Brusa, Jonas Dehairs, Johan Swinnen, Cyril Corbet, Yvan Larondelle and Olivier Feron ()
Additional contact information
Katarzyna Głowacka: UCLouvain
Sébastien Ibanez: UCLouvain
Ophélie Renoult: UCLouvain
Perrine Vermonden: UCLouvain
Maria Virginia Giolito: UCLouvain
Kübra Özkan: UCLouvain
Charline Degavre: UCLouvain
Léo Aubert: UCLouvain
Céline Guilbaud: UCLouvain
Florine Laloux-Morris: UCLouvain
Elena Richiardone: UCLouvain
Jérôme Ambroise: UCLouvain
Caroline Bouzin: UCLouvain
Davide Brusa: UCLouvain
Jonas Dehairs: KU Leuven and Leuven Cancer Institute (LKI)
Cyril Corbet: UCLouvain
Yvan Larondelle: UCLouvain
Olivier Feron: UCLouvain

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54435-3

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