Steatohepatitis-induced vascular niche alterations promote melanoma metastasis I

Despite recent advancements in melanoma therapy, hepatic metastasis in malignant melanoma patients remains associated with significantly reduced overall survival rates. Given the rising prevalence of metabolic liver diseases such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD/NASH), we investigated whether metabolic changes influence hepatic melanoma metastasis. Our study found that induction of advanced NASH in C57BL/6N mice through a choline-deficient L-amino acid (CDAA)-defined diet for ten weeks significantly increased hepatic metastasis, as demonstrated by injecting B16F10Luc2 and Wt31 melanoma cells. B16F10Luc2 cells showed heightened metastatic potential even with shorter periods of CDAA feeding before liver fibrosis developed. Conversely, hepatic steatosis induced by a high-fat diet alone did not promote increased melanoma metastasis. Early pre-fibrotic changes in the hepatic vascular niche, particularly in liver sinusoidal endothelial cells (LSECs), appeared to be responsible for the enhanced metastasis, characterized by continuous endothelial dedifferentiation and upregulation of adhesion molecules VCAM1, ICAM1, and E-selectin. Functionally, B16F10Luc2 cell retention in the hepatic vascular niche was significantly increased early after CDAA feeding, with ICAM1 inhibition leading to a notable reduction in cell retention. In summary, our findings highlight the hepatic vascular niche's sensitivity to metabolic alterations, suggesting potential avenues for preventing hepatic melanoma metastasis through angiotargeted therapies. 5 CDAA vs. 5 Chow were compared, with each n consisting of 3 pooled animals to obtain enough cells. Samples were pooled after organ harvesting and then LSEC isolation was performed. After isolation, RNA was extracted and sequenced and gene expression was analysed.