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.

Cancer Research UK Beatson Institute Glasgow UK

Department of Analytical Chemistry Faculty of Chemical Technology University of Pardubice Pardubice Czech Republic

Department of Gastroenterology Affiliated Hospital of Jiangsu University Jiangsu University Zhenjiang China

Department of Human Molecular Genetics and Biochemistry Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Imaging and Pathology Laboratory of Translational Cell and Tissue Research KU Leuven Leuven Belgium

Department of Oncology KU Leuven Leuven Belgium

Department of Pathology University Hospitals Leuven KU Leuven Leuven Belgium

Division of Translational Pediatric Sarcoma Research German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

Institute of Pathology Heidelberg University Hospital Heidelberg Germany

Laboratory for Angiogenesis and Vascular Metabolism VIB KU Leuven Leuven Belgium

Laboratory for Molecular Biology of Leukemia VIB KU Leuven Leuven Belgium

Laboratory for Molecular Cancer Biology VIB Center for Cancer Biology Leuven Belgium

Laboratory for Translational Breast Cancer Research Department of Oncology KU Leuven Leuven Belgium

Laboratory of Cellular Metabolism and Metabolic Regulation Department of Oncology KU Leuven and Leuven Cancer Institute Leuven Belgium

Laboratory of Cellular Metabolism and Metabolic Regulation VIB KU Leuven Center for Cancer Biology Leuven Belgium

Laboratory of Experimental Oncology Department of Oncology KU Leuven Leuven Belgium

Laboratory of Lipid Metabolism and Cancer Department of Oncology KU Leuven Leuven Belgium

Laboratory of Translational Genetics Department of Human Genetics KU Leuven Leuven Belgium

Laboratory of Translational Genetics VIB Center for Cancer Biology Leuven Belgium

Laboratory of Tumor Inflammation and Angiogenesis Center for Cancer Biology Department of Oncology KU Leuven Leuven Belgium

Laboratory of Tumor Inflammation and Angiogenesis VIB Center for Cancer Biology Leuven Belgium

School of Cancer Sciences University of Glasgow Glasgow UK

SciLifeLab Department of Microbiology Tumor and Cell Biology Karolinska Institute Solna Sweden

The Francis Crick Institute London UK

Université Paris Cité NF kappaB Différenciation et Cancer Paris France

Comment In

Nature. 2023 Mar;615(7951):224-225. doi: 10.1038/d41586-023-00538-8. PubMed

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