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

Metabolic rewiring is often considered an adaptive pressure limiting metastasis formation. However, some nutrients available in distant organs may inherently promote metastatic growth. We find that the lung and liver are lipid-rich environments. Moreover, we observe that premetastatic niche formation increases palmitate availability only in the lung, while high fat diet increases it in both organs. In line, 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 (CPT1a)-dependent manner. Concomitantly, lysine acetyltransferase 2a (KAT2a) expression is promoted by palmitate, linking the available acetyl-CoA to the acetylation of the NF-κB subunit p65. Deletion of KAT2a or CPT1a reduces metastasis formation in lean and high fat diet mice and patient-derived metastases from lipid rich organs show a co-expression of both proteins. In conclusion, palmitate-rich environments foster metastases growth by increasing p65 acetylation resulting in a pro-metastatic NF-κB signaling.