A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling

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 formati...

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Veröffentlicht in:NATURE CANCER 2023-03, Vol.4 (3), p.344-364
Hauptverfasser: Altea-Manzano, Patricia, Doglioni, Ginevra, Liu, Yawen, Cuadros, Alejandro M, Nolan, Emma, Fernández-García, Juan, Wu, Qi, Planque, Mélanie, Laue, Kathrin Julia, Cidre-Aranaz, Florencia, Liu, Xiao-Zheng, Marin-Bejar, Oskar, Van Elsen, Joke, Vermeire, Ines, Broekaert, Dorien, Demeyer, Sofie, Spotbeen, Xander, Idkowiak, Jakub, Montagne, Aurélie, Demicco, Margherita, Alkan, H Furkan, Rabas, Nick, Riera-Domingo, Carla, Richard, François, Geukens, Tatjana, De Schepper, Maxim, Leduc, Sophia, Hatse, Sigrid, Lambrechts, Yentl, Kay, Emily Jane, Lilla, Sergio, Alekseenko, Alisa, Geldhof, Vincent, Boeckx, Bram, de la Calle Arregui, Celia, Floris, Giuseppe, Swinnen, Johannes V, Marine, Jean-Christophe, Lambrechts, Diether, Pelechano, Vicent, Mazzone, Massimiliano, Zanivan, Sara, Cools, Jan, Wildiers, Hans, Baud, Véronique, Grünewald, Thomas G P, Ben-David, Uri, Desmedt, Christine, Malanchi, Ilaria, Fendt, Sarah-Maria
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Sprache:eng
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Zusammenfassung: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.
ISSN:2662-1347
2662-1347
DOI:10.1038/s43018-023-00513-2