Tumor metastasis to lymph node requires YAP-dependent metabolic adaptation

In cancer patients, metastasis of tumors to sentinel lymph nodes (LN) predicts disease progression and often guides treatment decisions. The mechanisms underlying tumor LN metastasis are poorly understood. Using comparative transcriptomics and metabolomics analyses of primary and LN metastatic tumors in mice, we found that LN metastasis requires that tumor cells undergo a metabolic shift toward fatty acid oxidation (FAO). Transcriptional co-activator yes-associated protein (YAP) is selectively activated in LN metastatic tumors, leading to upregulation of genes in the FAO signaling pathway. Pharmacological inhibition of FAO or genetic ablation of YAP suppressed LN metastasis in mice. Several bioactive bile acids were highly accumulated in the LN metastatic tumor. Inhibition of FAO or YAP may merit exploration as therapeutic strategies for mitigating tumor LN metastasis.