A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling
Authors listPatricia Altea-Manzano Ginevra Doglioni Yawen Liu Alejandro M Cuadros Emma Nolan Juan Fernández-García Qi Wu Mélanie Planque Kathrin Julia Laue Florencia Cidre-Aranaz Xiao-Zheng Liu Oskar Marin-Bejar Joke Van Elsen Ines Vermeire Dorien Broekaert Sofie Demeyer Xander Spotbeen Jakub Idkowiak Aurélie Montagne Margherita Demicco H Furkan Alkan Nick Rabas Carla Riera-Domingo François Richard Tatjana Geukens Maxim De Schepper Sophia Leduc Sigrid Hatse Yentl Lambrechts Emily Jane Kay Sergio Lilla Alisa Alekseenko Vincent Geldhof Bram Boeckx Celia de la Calle Arregui Giuseppe Floris Johannes V Swinnen Jean-Christophe Marine Diether Lambrechts Vicent Pelechano Massimiliano Mazzone Sara Zanivan Jan Cools Hans Wildiers Véronique Baud Thomas GP Grünewald Uri Ben-David Christine Desmedt Ilaria Malanchi Sarah-Maria Fendt
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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.
Journal Nature Cancer
Issue number 3