In vivo CRISPR activation screen identifies a lipid metabolism regulator as a driver of bone metastasis

The role of lipid metabolism in bone metastasis has not been documented. Here, by using an in vivo CRISPR activation screening system coupled with positive selection, we identify acyl-CoA binding protein (ACBP) as a previously undescribed bone metastasis driver. In non-metastatic cancer cells, overexpression of wild-type ACBP, but not the acyl-CoA binding deficient mutant, stimulates fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone-metastatic cells abrogates metastatic bone colonization. Mechanistically, ACBP-mediated FAO boosts ATP and NADPH production, reduces reactive oxygen species, and inhibits lipid peroxidation and ferroptosis. ACBP expression correlates with metabolic signaling, bone-metastatic ability, and poor clinical outcomes. Notably, FAO blockade or treatment with a ferroptosis inducer inhibits bone metastasis. Altogether, our findings reveal the role of lipid metabolism in tumor cell adaptation and thriving in the bone, and suggests that agents that target FAO or induce ferroptosis hold potential as bone metastasis drugs. Overall design: RNA sequencing (RNA-seq) of control and ACBP-knockout BoM-1833 cells cultured in the presence of oleic acid, an 18-carbon monounsaturated fatty acid, to gain insights into ACBP-regulated genes and pathways.