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In vivo CRISPR activation screen identifies acyl-CoA-binding protein as a driver of bone metastasis.

Hongqi Teng,Qinglei Hang,Caishang Zheng,Yuelong Yan,Shaomin Liu,Yang Zhao,Yalan Deng,Litong Nie,Weiche Wu,Marisela Sheldon,Zachary Yu,Wei Shi,Jianxuan Gao,Chenling Meng,Consuelo Martinez,Jie Zhang,Fan Yao,Yutong Sun,Di Zhao,Boyi Gan,Tong Meng,Li Ma

Published 2025 in Science Translational Medicine

ABSTRACT

One of the most common sites of cancer metastasis is to the bone. Bone metastasis is associated with substantial morbidity and mortality, and current therapeutic interventions remain largely palliative. Metastasizing tumor cells need to reprogram their metabolic states to adapt to the nutrient environment of distant organs; however, the role and translational relevance of lipid metabolism in bone metastasis remain unclear. Here, we used an in vivo CRISPR activation screening system coupled with positive selection to identify acyl-coenzyme A (CoA) binding protein (ACBP) as a bone metastasis driver. In nonmetastatic and weakly metastatic cancer cells, overexpression of wild-type ACBP, but not the acyl-CoA-binding deficient mutant, stimulated fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone metastatic cancer cells abrogated metastatic bone colonization. Mechanistically, ACBP-mediated FAO increased ATP and NADPH production, reduced reactive oxygen species, and inhibited lipid peroxidation and ferroptosis. We found that ACBP expression correlated with metabolic signaling, bone metastatic ability, and poor clinical outcomes. In mouse models, pharmacological blockade of FAO or treatment with a ferroptosis inducer inhibited bone metastasis. Together, our findings reveal the role of lipid metabolism in tumor cells adapting and thriving in the bone and identify ACBP as a key regulator of this process. Agents that target FAO or induce ferroptosis represent a promising therapeutic approach for treating bone metastases.

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