Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation

Abstract

In cancer patients, metastasis of tumors to sentinel lymph nodes (LNs) predicts disease progression and often guides treatment decisions. The mechanisms underlying tumor LN metastasis are poorly understood. By 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 coactivator yes-associated protein (YAP) is selectively activated in LN-metastatic tumors, leading to the up-regulation 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 accumulated to high levels in the metastatic LNs, and these bile acids activated YAP in tumor cells, likely through the nuclear vitamin D receptor. Inhibition of FAO or YAP may merit exploration as a potential therapeutic strategy for mitigating tumor metastasis to LNs.

A Mouse Homolog of a Human TP53 Germline Mutation Reveals a Lipolytic Activity of p53

“…The increased expression of arachidonic acid metabolism genes may also promote breast cancer growth through generation of eicosanoids ( Figure S6A; Jiang et al, 2005;Mitra et al, 2011). Consistent with the elevated lipolytic activity, bile acid metabolites were the most highly increased compounds identified in p53 178C/C plasma and have been reported to mediate tumor metastasis to lymph nodes ( Figure S5B; Lee et al, 2019). There are limited data on the physiological effects of germline LFS mutations, but our p53 178C/C mouse model reveals an activity of a relatively common LFS mutation that regulates basal metabolism and may also affect cancer development.…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 110 ] YAP shRNA also reduced the ability of B16F10 melanoma cells to spread to lymph nodes following implantation into footpads. [ 111 ] YAP shRNA knockdown reduced, and YAP 5SA overexpression increased, the expression of PD‐L1 in treatment‐resistant melanoma cells (A375SM), suppressing T‐cell killing. [ 112 ] Thus, the evidence from cell lines supports a possible role for YAP/TAZ in melanoma metastasis and resistance to immunotherapy.…”

Ovarian Cancer—Why Lipids Matter

“…Aside from metastatic ovarian cancer, altered lipid metabolism was also observed as a regulator of tumor metastasis to lymph nodes in melanoma by Lee et al [61]. The authors utilized subcutaneous xenograft models and compared cells isolated from the primary tumor site versus micrometastatic and macrometastatic tumor-draining lymph nodes.…”