YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice

Lu, Xiaozhi; Peng, Baogang; Chen, Ge; Pes, Giovanni Mario; Ribback, Silvia; Ament, Cindy; Xu, Hui; Pal, Rajesh; Rodrigues, Pedro M.; Evert, Matthias; Calvisi, Diego F.; Chen, Xin; Fan, Biao; Wang, Jingxiao

doi:10.1016/j.ajpath.2021.05.017

Cited by 13 publications

(5 citation statements)

References 65 publications

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“…Specifically, the Hippo downstream effector YAP is aberrantly activated virtually in all iCCA cases [ 25 , 31 ]. Furthermore, YAP cooperates with AKT and NOTCH1 to induce iCCA development in the mouse liver [ 37 , 45 ]. However, the reports on the involvement of the YAP paralog TAZ in this disease are scanty.…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

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Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined. Methods We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP. Results Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis. Conclusions Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis

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Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

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“…An increase of Dusp4 and Dusp6 transcripts was detected. Similarly, a statistically significant difference for Dusp4 expression was observed in the NICD/NRAS CCA model [47] compared to EV (adj p = 0.023, Kruskal-Wallis test, Dunn's multiple comparisons). No statistically significant difference was observed in the NICD only and NICD/AKT models [48].…”

Section: Kras Mutations In Cca Cell Lines and Human Samples And Nras ...mentioning

confidence: 71%

Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis

Klemm,

Evert,

Utpatel

et al. 2023

BMC Cancer

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Background Upregulation of the mitogen-activated protein kinase (MAPK) cascade is common in hepatocellular carcinoma (HCC). Neuroblastoma RAS viral oncogene homolog (NRAS) is mutated in a small percentage of HCC and is hitherto considered insufficient for hepatocarcinogenesis. We aimed to characterize the process of N-Ras-dependent carcinogenesis in the liver and to identify potential therapeutic vulnerabilities. Methods NRAS V12 plasmid was delivered into the mouse liver via hydrodynamic tail vein injection (HTVI). The resulting tumours, preneoplastic lesions, and normal tissue were characterized by NanoString® gene expression analysis, Western Blot, and Immunohistochemistry (IHC). The results were further confirmed by in vitro analyses of HCC cell lines. Results HTVI with NRAS V12 plasmid resulted in the gradual formation of preneoplastic and neoplastic lesions in the liver three months post-injection. These lesions mostly showed characteristics of HCC, with some exceptions of spindle cell/ cholangiocellular differentiation. Progressive upregulation of the RAS/RAF/MEK/ERK signalling was detectable in the lesions by Western Blot and IHC. NanoString® gene expression analysis of preneoplastic and tumorous tissue revealed a gradual overexpression of the cancer stem cell marker CD133 and Dual Specificity Phosphatases 4 and 6 (DUSP4/6). In vitro, transfection of HCC cell lines with NRAS V12 plasmid resulted in a coherent upregulation of DUSP4 and DUSP6. Paradoxically, this upregulation in PLC/PRF/5 cells was accompanied by a downregulation of phosphorylated extracellular-signal-regulated kinase (pERK), suggesting an overshooting compensation. Silencing of DUSP4 and DUSP6 increased proliferation in HCC cell lines. Conclusions Contrary to prior assumptions, the G12V NRAS mutant form is sufficient to elicit hepatocarcinogenesis in the mouse. Furthermore, the upregulation of the MAPK cascade was paralleled by the overexpression of DUSP4, DUSP6, and CD133 in vivo and in vitro. Therefore, DUSP4 and DUSP6 might fine-tune the excessive MAPK activation, a mechanism that can potentially be harnessed therapeutically.

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“…Others did not detect CCA-neoplastic or -dysplastic areas at least at 52 weeks of age [ 7 ]. In our hands, progressive expression of markers of hepatoblast differentiation and Notch signaling, which, together with Yap, is a key pathway in cholangiocarcinogenesis [ 38 , 39 ], were detected already in 52-week-old Jnk ∆ hepa mice in the absence of neoplastic lesions on their liver surface. Importantly, nodules were visible in the surface of TAA- and DEN/CCl 4 Jnk ∆hepa -treated mice livers, as well as the presence of markers of biliary epithelium atypia and cholangiocarcinogenesis, such as the activation of Notch1 and Yap pathways.…”

Section: Discussionmentioning

confidence: 94%

Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

Chen

et al. 2021

Cancers

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Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.

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YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice

Cited by 13 publications

References 65 publications

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis

Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

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