Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources
(2024) Nature Communications — Vol. 15, n° 1, p. 10107 [1-16] (2024)
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- 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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Glowacka, K., Ibanez, S., Renoult, O., Vermonden, P., Degavre, C., Giolito, M. V., Aubert, L., Özkan, K., Guilbaud, C., Richiardone, E., Laloux-Morris, F., Ambroise, J., Bouzin, C., Brusa, D., Dehairs, J., Swinnen, J., Corbet, C., Larondelle, Y., & Feron, O. (2024). Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources. Nature Communications, 15(1), 10107 [1-16]. https://doi.org/10.1038/s41467-024-54435-3 (Original work published 2024)