Study of a new driver and therapeutic vulnerability of bone metastasis

Current therapeutic interventions remain largely palliative in patients with bone metastases. For instance, treatment with zoledronic acid or denosumab can inhibit bone resorption, reduce the risk of skeletal-related events, and alleviate bone pain; however, their clinical use for bone metastasis is insufficient. Our research addresses the urgent need to transform bone metastasis treatment by exploring a new driver and therapeutic vulnerability of bone metastasis. Leveraging an in vivo positive selection system based on CRISPR activation, we conducted a forward genetics screen that led to the discovery of a bone metastasis driver, acyl-CoA binding protein (ACBP), whose role in cancer metastasis has not been reported previously. In preliminary studies, overexpression of wild-type ACBP, but not the acyl-CoA-binding deficient mutant, in non-metastatic and weakly metastatic cancer cells stimulated fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone-metastatic breast cancer cells abrogated metastatic bone colonization. Moreover, overexpression of ACBP in cancer cells boosted the production of ATP and NADPH, reduced levels of reactive oxygen species, and inhibited lipid peroxidation and ferroptotic cell death (ferroptosis). Notably, we found a significant correlation of ACBP expression with metabolic signaling, bone metastases, and poor clinical outcomes. Building upon our preliminary findings, we will study the function and mechanism of action of ACBP in breast cancer bone metastasis, as well as its therapeutic potential. Specifically, we will test the hypothesis that ACBP promotes bone metastasis by regulating lipid metabolism – stimulating FAO while protecting against lipid peroxidation and ferroptosis. In addition to tumor cell-autonomous effects, we will investigate ACBP’s role in intercellular communication, such as whether bone marrow adipocytes transfer fatty acids to ACBP-expressing breast cancer cells and whether ACBP propagates FAO activation between tumor cells. Moreover, we will examine the impact of ACBP on the tumor microenvironment at primary and bone-metastatic sites, focusing on the recruitment of specific populations of immune cells and stromal cells. Further, we will explore whether blocking FAO or neutralizing ACBP through targeted therapeutic agents can inhibit breast cancer bone metastasis. If successful, this project could illuminate new pathways through which tumor cells adapt to and thrive in the bone, providing insights that may guide the development of novel therapies targeting bone metastasis in breast cancer and other cancers.