학술논문
A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling
Document Type
Original Paper
Author
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
Source
Nature Cancer. 4(3):344-364
Subject
Language
English
ISSN
2662-1347
Abstract
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.
Fendt and colleagues find that pre-metastatic niche formation and a high-fat diet increase palmitate availability in future organs of metastases and show that breast cancer cells use palmitate to generate acetyl-CoA, acetylate the NF-κB subunit p65 and induce pro-metastatic signaling.
Fendt and colleagues find that pre-metastatic niche formation and a high-fat diet increase palmitate availability in future organs of metastases and show that breast cancer cells use palmitate to generate acetyl-CoA, acetylate the NF-κB subunit p65 and induce pro-metastatic signaling.