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Project description:Background & aimsIntrahepatic cholangiocarcinoma (ICC) is a devastating liver cancer with extremely high intra- and inter-tumoral molecular heterogeneity, partly due to its diverse cellular origins. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development.MethodsExpression of ICC driver genes in human diseased livers at risk for ICC development were examined. The sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SRY-box transcription factor 9 (SOX9) and yes-associated protein 1 (YAP1) in HC-driven ICC. We identified DNA methyltransferase 1 (DNMT1) as a YAP1 target, which was validated by loss- and gain-of-function studies, and its mechanism addressed by chromatin immunoprecipitation sequencing.ResultsCo-expression of AKT and Notch intracellular domain (NICD)/YAP1 in HC yielded ICC that represents 13% to 29% of clinical ICC. NICD independently regulates SOX9 and YAP1 and deletion of either, significantly delays ICC development. Yap1 or TEAD inhibition, but not Sox9 deletion, impairs HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate switch through the repression of HC-specific genes regulated by master regulators for HC differentiation, including hepatocyte nuclear factor 4 alpha, hepatocyte nuclear factor 1 alpha, and CCAAT/enhancer-binding protein alpha/beta. DNMT1 loss prevented NOTCH/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in a subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development.ConclusionWe identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-to-BEC/ICC conversion, which may be relevant in cholestasis-to-ICC pathogenesis in the clinic.
| S-EPMC9329208 | biostudies-literature
Project description:We reported the transcritpome in the healthy control liver of wild-type mice, liver bearing myrAKT-NICD driven ICC and livers bearing myrAKT-YAP driven Sox9 deleted HCC from liver-specific Sox9 knockout mice
2023-07-25 | GSE145900 | GEO
Project description:BACKGROUND AND AIM: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. A critical barrier to developing an effective regimen for ICC is its intra- and inter-tumoral molecular heterogeneity, which may in part be due to its diverse cellular origin. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development. METHODS: Expression of ICC driver genes in human diseased livers at risk for ICC development were examined. Sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SOX9 and YAP1 in HC-driven ICC. These models and in silico studies led to identification of DNA methyltransferase-1 (DNMT1) as a YAP1 target, which was validated by both loss- and gain-of-function studies. RESULTS: Co-expression of AKT along with NICD/YAP1 in HC yielded ICC which resembled proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD induced SOX9 and YAP1 in HC-driven ICC and deletion of either significantly delays ICC development. Yap1 deletion or TEAD inhibition, but not Sox9 deletion, impaired HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development. CONCLUSION: We identify a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for of HC-to-BEC/ICC conversion, may be relevant in cholestasis-to-ICC pathogenesis in the clinic.
2023-07-25 | GSE200468 | GEO
Project description:BACKGROUND AND AIM: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. A critical barrier to developing an effective regimen for ICC is its intra- and inter-tumoral molecular heterogeneity, which may in part be due to its diverse cellular origin. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development. METHODS: Expression of ICC driver genes in human diseased livers at risk for ICC development were examined. Sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SOX9 and YAP1 in HC-driven ICC. These models and in silico studies led to identification of DNA methyltransferase-1 (DNMT1) as a YAP1 target, which was validated by both loss- and gain-of-function studies. RESULTS: Co-expression of AKT along with NICD/YAP1 in HC yielded ICC which resembled proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD induced SOX9 and YAP1 in HC-driven ICC and deletion of either significantly delays ICC development. Yap1 deletion or TEAD inhibition, but not Sox9 deletion, impaired HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development. CONCLUSION: We identify a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for of HC-to-BEC/ICC conversion, may be relevant in cholestasis-to-ICC pathogenesis in the clinic.
2023-07-25 | GSE200471 | GEO
Project description:NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma
| PRJNA824781 | ENA
Project description:NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma [ChIP-Seq]
| PRJNA824732 | ENA
Project description:NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma [RNA-Seq]
| PRJNA608694 | ENA
Project description:NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma [bulk RNA-Seq]
| PRJNA824783 | ENA
Project description:Intrahepatic cholangiocarcinoma (ICC) is a malignant epithelial neoplasm composed of cells resembling cholangiocytes that line the intrahepatic bile ducts in portal areas of the hepatic lobule. Although ICC has been defined as a tumor arising from cholangiocyte transformation, recent evidence from genetic lineage-tracing experiments has indicated that hepatocytes can be a cellular origin of ICC by directly changing their fate to that of biliary lineage cells. Notch signaling has been identified as an essential factor for hepatocyte conversion into biliary lineage cells at the onset of ICC. However, the mechanisms underlying Notch signal activation in hepatocytes remain unclear. Here, using a mouse model of ICC, we found that hepatic macrophages called Kupffer cells transiently congregate around the central veins in the liver and express the Notch ligand Jagged-1 coincident with Notch activation in pericentral hepatocytes. Depletion of Kupffer cells prevents the Notch-mediated cell-fate conversion of hepatocytes to biliary lineage cells, inducing hepatocyte apoptosis and increasing mortality in mice. These findings will be useful for uncovering the pathogenic mechanism of ICC and developing prevenient and therapeutic strategies for this refractory disease.
| S-EPMC5048166 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development and progression. Our aim was to investigate the effectiveness of Crenigacestat, a selective inhibitor of NOTCH1 signaling, against the cross-talk between cancer cells and the surrounding ecosystem in an in vivo HuCCT1-xenograft model. In the present study, a transcriptomic analysis approach, validated by Western blotting and qRT-PCR on iCCA tumor masses treated with Crenigacestat, was used to study the molecular pathways responsive to drug treatment. Our results indicate that Crenigacestat significantly inhibited NOTCH1 and HES1, whereas tumor progression was not affected. In addition, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions. Therefore, although these data need further investigation, our observations confirm that Crenigacestat selectively targets NOTCH1 and that the desmoplastic response in iCCA likely plays a key role in both drug effectiveness and tumor progression.
| S-EPMC9032805 | biostudies-literature