A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling.
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Altea-Manzano P, Doglioni G, Liu Y, Cuadros AM, Nolan E, Fernández-García J, Wu Q, Planque M, Laue KJ, Cidre-Aranaz F, Liu XZ, Marin-Bejar O, Van Elsen J, Vermeire I, Broekaert D, Demeyer S, Spotbeen X, Idkowiak J, Montagne A, Demicco M, Alkan HF, Rabas N, Riera-Domingo C, Richard F, Geukens T, De Schepper M, Leduc S, Hatse S, Lambrechts Y, Kay EJ, Lilla S, Alekseenko A, Geldhof V, Boeckx B, de la Calle Arregui C, Floris G, Swinnen JV, Marine JC, Lambrechts D, Pelechano V, Mazzone M, Zanivan S, Cools J, Wildiers H, Baud V, Grünewald TGP, Ben-David U, Desmedt C, Malanchi I, Fendt SM
Nat Cancer 4 (3) 344-364 [2023-03-00; online 2023-02-02]
Metabolic rewiring is often considered an adaptive pressure limiting metastasis formation; however, some nutrients available at distant organs may inherently promote metastatic growth. We find that the lung and liver are lipid-rich environments. Moreover, we observe that pre-metastatic niche formation increases palmitate availability only in the lung, whereas a high-fat diet increases it in both organs. In line with this, targeting palmitate processing inhibits breast cancer-derived lung metastasis formation. Mechanistically, breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a-dependent manner. Concomitantly, lysine acetyltransferase 2a expression is promoted by palmitate, linking the available acetyl-CoA to the acetylation of the nuclear factor-kappaB subunit p65. Deletion of lysine acetyltransferase 2a or carnitine palmitoyltransferase 1a reduces metastasis formation in lean and high-fat diet mice, and lung and liver metastases from patients with breast cancer show coexpression of both proteins. In conclusion, palmitate-rich environments foster metastases growth by increasing p65 acetylation, resulting in a pro-metastatic nuclear factor-kappaB signaling.
PubMed 36732635
DOI 10.1038/s43018-023-00513-2
Crossref 10.1038/s43018-023-00513-2
pii: 10.1038/s43018-023-00513-2