Steatohepatitis-induced vascular niche alterations promote melanoma metastasis II. Steatohepatitis-induced vascular niche alterations promote melanoma metastasis II

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. Overall design: 4 CDAA vs. 4 Chow were compared. RNA was extracted from cryo-tissue, sequenced and gene expression was analysed.

尽管黑色素瘤治疗（melanoma therapy）领域近年来取得诸多进展，但恶性黑色素瘤（malignant melanoma）患者发生肝转移（hepatic metastasis）仍与显著降低的总生存率（overall survival rates）密切相关。鉴于非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）与非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）等代谢性肝病的患病率持续攀升，本研究旨在探究代谢改变是否会影响黑色素瘤肝转移。本研究通过为期10周的胆碱缺乏L-氨基酸（choline-deficient L-amino acid, CDAA）定制饲料，在C57BL/6N小鼠中诱导进展期NASH（advanced NASH）；通过向小鼠注射B16F10Luc2与Wt31黑色素瘤细胞，证实该模型小鼠的肝转移发生率显著升高。即便在肝纤维化（liver fibrosis）发生前的较短CDAA饲料喂养周期内，B16F10Luc2细胞即表现出增强的转移潜能。与之相反，仅通过高脂饮食（high-fat diet）诱导的肝脂肪变性（hepatic steatosis）并未促进黑色素瘤肝转移发生率升高。肝血管微环境（hepatic vascular niche）的早期纤维化前改变，尤其是肝窦内皮细胞（liver sinusoidal endothelial cells, LSECs）似乎是转移增强的关键诱因，其特征为内皮细胞持续去分化（endothelial dedifferentiation）以及黏附分子（adhesion molecules）VCAM1、ICAM1与E-选择素（E-selectin）的表达上调。功能实验显示，CDAA饲料喂养早期，B16F10Luc2细胞在肝血管微环境中的细胞滞留（retention）显著升高，而抑制ICAM1可显著降低细胞滞留率。综上，本研究结果凸显了肝血管微环境对代谢改变的敏感性，提示可通过血管靶向治疗（angiotargeted therapies）实现黑色素瘤肝转移的潜在防治途径。实验设计：设置4组CDAA饲料喂养小鼠与4组常规维持饲料（Chow）喂养小鼠。从冰冻组织（cryo-tissue）中提取RNA，进行测序并分析基因表达（gene expression）。