Tumor metastasis to lymph node requires metabolic reprogramming toward fatty acid oxidation

Abstract

Metastasis of tumors to a sentinel lymph node (LN) is a strong predictor of cancer patient mortality and determinant of disease progression and treatment options. Despite the clinical significance of tumor LN metastasis, the mechanisms underlying this process remain largely unexplored. Using comparative transcriptomics and metabolomics analyses of the primary tumor and LN micro- and macro-metastatic tumors, we found that tumor cells undergo dramatic metabolic shift towards fatty acid oxidation (FAO) for successful LN metastasis. Mechanistically, transcription co-activator YAP is selectively activated in LN metastatic tumors, leading to stimulation of FAO gene programs. Pharmacological inhibition of FAO or genetic ablation of YAP in tumors markedly suppressed LN metastasis. Unexpectedly, metastatic tumors highly stimulated the bile acid synthesis pathway upon arrival at the LN, and these bile acids activated YAP of tumor cells via nuclear vitamin D receptor. This study propose that inhibition of FAO or YAP signaling to prevent the metabolic adaptation of metastatic tumors offers a potential therapeutic strategy for mitigating tumor LN metastasis.