2. Academic Validation
  3. A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling

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

  • Nat Cancer. 2023 Feb 2. doi: 10.1038/s43018-023-00513-2.
Patricia Altea-Manzano 1 2,  Ginevra Doglioni # 1 2,  Yawen Liu # 1 2 3,  Alejandro M Cuadros 1 2,  Emma Nolan 4,  Juan Fernández-García 1 2,  Qi Wu 1 2 5,  Mélanie Planque 1 2,  Kathrin Julia Laue 6,  Florencia Cidre-Aranaz 7 8,  Xiao-Zheng Liu 1 2,  Oskar Marin-Bejar 9 10,  Joke Van Elsen 1 2,  Ines Vermeire 1 2,  Dorien Broekaert 1 2,  Sofie Demeyer 11,  Xander Spotbeen 12,  Jakub Idkowiak 12 13,  Aurélie Montagne 14,  Margherita Demicco 1 2,  H Furkan Alkan 1 2,  Nick Rabas 4,  Carla Riera-Domingo 15 16,  François Richard 17,  Tatjana Geukens 17,  Maxim De Schepper 17,  Sophia Leduc 17,  Sigrid Hatse 5,  Yentl Lambrechts 5,  Emily Jane Kay 18,  Sergio Lilla 18,  Alisa Alekseenko 19,  Vincent Geldhof 20,  Bram Boeckx 21 22,  Celia de la Calle Arregui 1 2,  Giuseppe Floris 23 24,  Johannes V Swinnen 12,  Jean-Christophe Marine 9 10,  Diether Lambrechts 21 22,  Vicent Pelechano 19,  Massimiliano Mazzone 15 16,  Sara Zanivan 18 25,  Jan Cools 11,  Hans Wildiers 5,  Véronique Baud 14,  Thomas G P Grünewald 7 8 26,  Uri Ben-David 6,  Christine Desmedt 17,  Ilaria Malanchi 4,  Sarah-Maria Fendt 27 28
Affiliations

Affiliations

  • 1 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
  • 2 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • 3 Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China.
  • 4 The Francis Crick Institute, London, UK.
  • 5 Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 6 Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 7 Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • 8 Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 9 Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, Leuven, Belgium.
  • 10 Department of Oncology, KU Leuven, Leuven, Belgium.
  • 11 Laboratory for Molecular Biology of Leukemia, VIB-KU Leuven, Leuven, Belgium.
  • 12 Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 13 Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Pardubice, Czech Republic.
  • 14 Université Paris Cité, NF-kappaB, Différenciation et Cancer, Paris, France.
  • 15 Laboratory of Tumor Inflammation and Angiogenesis, VIB Center for Cancer Biology, Leuven, Belgium.
  • 16 Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 17 Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 18 Cancer Research UK Beatson Institute, Glasgow, UK.
  • 19 SciLifeLab, Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solna, Sweden.
  • 20 Laboratory for Angiogenesis and Vascular Metabolism, VIB-KU Leuven, Leuven, Belgium.
  • 21 Laboratory of Translational Genetics, VIB Center for Cancer Biology, Leuven, Belgium.
  • 22 Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • 23 Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium.
  • 24 Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
  • 25 School of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 26 Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 27 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium. sarah-maria.fendt@kuleuven.be.
  • 28 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. sarah-maria.fendt@kuleuven.be.
  • # Contributed equally.
PMID: 36732635 DOI: 10.1038/s43018-023-00513-2
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.

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