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
  • 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. [email protected].
  • 28. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. [email protected].
  • # 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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