Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources
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.
Authors
- Cyril Corbet (ORCID: https://orcid.org/0000-0001-8795-9131)
- Elena Richiardone
- Jonas Dehairs (ORCID: https://orcid.org/0000-0002-6789-2264)
- Maria Virginia Giolito (ORCID: https://orcid.org/0000-0002-4888-7857)
- Yvan Larondelle (ORCID: https://orcid.org/0000-0001-7770-6747)
- Johannes V. Swinnen (ORCID: https://orcid.org/0000-0002-7720-5077)
- Kübra Özkan (ORCID: https://orcid.org/0000-0003-0580-5804)
- Charline Degavre
- Caroline Bouzin (ORCID: https://orcid.org/0000-0003-0694-1947)
- Céline Guilbaud
- Olivier Féron (ORCID: https://orcid.org/0000-0001-5360-0286)
- Ophélie Renoult (ORCID: https://orcid.org/0000-0003-0916-8611)
- Davide Brusa (ORCID: https://orcid.org/0000-0002-6499-9648)
- Perrine Vermonden
- Sébastien Ibanez
- Jérôme Ambroise (ORCID: https://orcid.org/0000-0002-1218-6143)
- Léo Aubert (ORCID: https://orcid.org/0000-0003-1499-0853)
- Katarzyna Głowacka (ORCID: https://orcid.org/0000-0002-8892-1482)
- Florine Laloux-Morris
Institutions
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Directorate-General Joint Research Centre (BE)
- UCLouvain (BE)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1038/s41467-024-54435-3
- Citations
- 7
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.00
Funders
- Université Catholique de Louvain
- Fonds De La Recherche Scientifique - FNRS
- KU Leuven
- Fondation contre le Cancer
- Walloon excellence in life sciences and biotechnology