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

Patricia 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 DemiccoH. 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 G.P. Grünewald, Uri Ben-David, Christine Desmedt, Ilaria Malanchi, Sarah Maria Fendt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish
Pages (from-to)344-364
Number of pages21
JournalNature Cancer
Volume4
Issue number3
DOIs
StatePublished - Mar 2023

Funding

FundersFunder number
Belgian Foundation Against CancerC/2020/1441
Beug Foundation
FATLAS101003153
Stand Up to Cancer campaign for CRUKA29800
University Hospitals from Leuven14/21/114, KOOR 2021
Wallenberg AcademyKAW 2016.0123
Ragnar Söderbergs stiftelse
Gilead Foundation
Breast Cancer Now2019AugPR1307
Wellcome Trust
Fondation CancerFC/2018/07
Barbara und Wilfried Mohr-Stiftung
HORIZON EUROPE Marie Sklodowska-Curie Actions
Medical Research Council
Cancer Research UKFC001112
European Research CouncilCoG-2020-725492
Fonds Wetenschappelijk OnderzoekA17196, 665501, 773208
KU Leuven771486, G0B4122N
Karolinska Institutet
VetenskapsrådetVR 2020-01480
China Scholarship Council
Stichting Tegen Kanker
Fondation Nelia et Amadeo Barletta
Science for Life Laboratory
Fonds Baillet Latour
Université de Paris

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