Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity.

Metastatic tumor cells exhibit distinct metabolic flexibility in overcoming different microenvironmental obstacles and thriving in a secondary organ; thus, metabolic vulnerabilities can potentially be targeted. It was reported that mitochondrial biogenesis and dynamics play crucial roles in disseminated tumor cells satisfying their energy demands and metabolic plasticity. However, the detailed molecular mechanism by which mitochondrial dynamics promotes tumor metastasis is still unclear. Herein, we identified that metastatic breast cancer cells exhibited increased lipid contents in mitochondria and promoted a metabolic shift towards fatty acid oxidation (FAO). The increased FAO was accompanied by promotion of mitochondrial fission. Mechanistically, we found that upregulation of DEAD-box polypeptide 3, X-linked (DDX3) promoted mitochondrial fission and facilitated FAO. Suppression of DDX3 diminished FAO and elicited mitochondrial oxidative stress in metastatic tumor cells. Moreover, DDX3 mediated dynamin-related protein 1 (DRP1) phosphorylation at S616 through collaborating with cyclin-dependent kinase 1 (CDK1). Inhibition of the DDX3-DRP1-CDK1 axis reduced cancer stemness properties and tumor metastasis. Our findings indicate that DDX3 modulates mitochondrial plasticity to drive metabolic adaptation in breast tumor metastasis. DDX3 provides a potential diagnostic biomarker and therapeutic vulnerability through which cancer metabolism can be targeted.