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.脂质代谢在骨转移中的作用尚未见诸报道。本研究采用体内CRISPR激活筛选系统联合阳性筛选策略，鉴定出酰基辅酶A结合蛋白（acyl-CoA binding protein, ACBP）作为此前未被报道的骨转移驱动因子。在非转移性癌细胞中，过表达野生型ACBP（而非酰基辅酶A结合缺陷突变体）可促进脂肪酸氧化（fatty acid oxidation, FAO）与骨转移进程；反之，在高骨转移癌细胞中敲除ACBP则可阻断其骨定植转移能力。机制上，ACBP介导的脂肪酸氧化可促进ATP与NADPH生成，降低活性氧水平，同时抑制脂质过氧化与铁死亡（ferroptosis）。ACBP的表达水平与代谢信号通路、骨转移能力及不良临床预后显著相关。值得注意的是，脂肪酸氧化阻断剂或铁死亡诱导剂均可抑制骨转移。综上，本研究揭示了脂质代谢在肿瘤细胞适应并存活于骨微环境中的关键作用，并提示靶向脂肪酸氧化或诱导铁死亡的制剂具备成为骨转移治疗药物的潜力。 实验整体设计：对在含油酸（一种18碳单不饱和脂肪酸）的培养基中培养的对照组与ACBP敲除型BoM-1833细胞进行RNA测序（RNA-seq），以解析ACBP调控的基因与信号通路。