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Steatohepatitis-induced vascular niche alterations promote melanoma metastasis I

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE264249 | GEO | 2025/02/05

REPOSITORIES: GEO

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Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

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Steatohepatitis-induced vascular niche alterations promote melanoma metastasis I

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