Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice

Wang, Jingxiao; Dong, Mingjie; Xu, Zhenhe; Song, Xinhua; Zhang, Shanshan; Qiao, Yu; Che, Li; Gordan, John D.; Hu, Kaiwen; Liu, Yan; Calvisi, Diego F.; Chen, Xin

doi:10.1038/s41388-018-0188-1

Cited by 82 publications

(84 citation statements)

References 45 publications

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“…In this regard, experimental overexpression of the intracellular domain of NOTCH1 receptor (NICD1) in hepatocytes has been associated with the development of iCCA in mouse models 79,80,158 . Similarly, inhibition of NOTCH2, the expression of which has been shown to be related to well-differentiated iCCA 155 , markedly reduced tumour burden in various mouse models of liver cancer (including iCCA) 81,159 , whereas overexpression of NOTCH3 was associated with the development and progression of iCCA, promot ing cell survival via PI3K-AKT signalling 160 . Several Notch inhibitors are being developed, and their availability increases interest in this pathway 161 .…”

Section: Chemoresistance and Survivalmentioning

confidence: 95%

“…Controversies exist regarding the cellular origins of iCCA based on lineage tracing studies in experimental carcinogenetic models 76 . Indeed, there is evidence in favour of HpSC, cholangiocyte or hepatocyte origin of iCCA from these experimental settings [76][77][78][79][80][81] . Thus, a definitive determination of the origin of iCCA in humans cannot be reached based on current evidence and requires further research.…”

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confidence: 99%

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Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Bañales

Marin

Lamarca

et al. 2020

Nat Rev Gastroenterol Hepatol

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1,253

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Cholangiocarcinoma (CCA) constitutes a diverse group of malignancies emerging in the biliary tree. CCAs are divided into three subtypes depending on their anatomical site of origin: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) CCA 1,2 (Fig. 1). Of note, considered as an independent entity, mixed HCC-CCA tumours are a rare type of liver malignancy sharing features of both iCCA and HCC and presenting an aggressive disease course and poor prognosis 3,4. iCCAs arise above the second-order bile ducts, whereas the point of anatomical distinction between pCCA and dCCA is the insertion of the cystic duct. pCCA and dCCA can also be collectively referred to as 'extrahepatic' (eCCA) 5. In the USA, pCCA is the single largest group, accounting for approximately 50-60% of all CCAs, followed by dCCA (20-30%) and iCCA (10-20%) 1,6,7. CCA is the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC), comprising approximately 15% of all primary liver tumours and 3% of gastrointestinal cancers 1,6,7. CCAs are usually asymptomatic in early stages and, therefore, often diagnosed when the disease is already in advanced stages, which highly compromises therapeutic options, resulting in a dismal prognosis 1,8. CCA is a rare cancer, but its incidence (0.3-6 per 100,000 inhabitants per year) 1 and mortality (1-6 per 100,000 inhabitants per year, globally 9 , not taking into account specific regions with incidence >6 per 100,000 habitants such as South Korea, China and Thailand) have been increasing in the past few decades worldwide, representing a global health problem. Despite advances in

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Section: Chemoresistance and Survivalmentioning

confidence: 95%

mentioning

confidence: 99%

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Bañales

Marin

Lamarca

et al. 2020

Nat Rev Gastroenterol Hepatol

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1,253

1,273

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“…The plasmids used for mouse injection, including pT3-EF1α, pT3-EF1α-c-Met (human c-Met or hMet), pT3-EF1α-β-CateninS45Y, pT3-EF1α-ΔN90-β-Catenin, pT3-EF1α-dnRBPJ (with Nter minal V5 tag), phosphorylated cytomegalovirus (pCMV), pCMV-Cre, and pCMV/sleeping beauty transposase, have been described in our publications. (12)(13)(14) pX330-U6-Chimeric_BB-CBh-hSpCas9 (pX330) and pLentiCRISPRv2_Puro plasmids were obtained from Addgene (#42230 and #98290, respectively). To delete Axin1 in the mouse liver, we constructed pX330 plasmids expressing single-guide RNAs (sgRNAs) against mouse Axin1 (NM_001159598.1).…”

Section: Constructs and Reagentsmentioning

confidence: 99%

Axis inhibition protein 1 (Axin1) Deletion–Induced Hepatocarcinogenesis Requires Intact β‐Catenin but Not Notch Cascade in Mice

et al. 2019

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Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/β‐Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/β‐catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c‐MET activation and AXIN1 mutations occur concomitantly in ~3%‐5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9‐based gene deletion of Axin1 (sgAxin1) in combination with transposon‐based expression of c‐Met in the mouse liver (c‐Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c‐Met/sgAxin1, and HCCs induced by c‐Met/∆N90‐β‐Catenin revealed activation of the Wnt/β‐Catenin and Notch signaling in c‐Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/β‐Catenin target genes were induced in c‐Met/sgAxin1 HCC when compared with corresponding lesions from c‐Met/∆N90‐β‐Catenin mice. To study whether endogenous β‐Catenin is required for c‐Met/sgAxin1‐driven HCC development, we expressed c‐Met/sgAxin1 in liver‐specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β‐Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal‐binding protein for immunoglobulin kappa J region (RBP‐J) or the ablation of Notch2 did not significantly affect c‐Met/sgAxin1‐driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c‐Met to induce HCC in mice, in a β‐Catenin signaling–dependent but Notch cascade–independent way.

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“…In this regard, Wang et al explored the role of Notch cascade in AKT/Yap iCCA tumors. The authors confirmed that the Notch signaling pathway is activated in iCCA: in particular Notch2 is the main influencer, whereas inactivation of Notch1 slightly delays tumor development [184].…”

Section: Hydrodynamic Transfection For Generation Of Mouse Modelsmentioning

confidence: 68%

Evolution of the Experimental Models of Cholangiocarcinoma

Massa

Varamo

Vita

et al. 2020

Cancers

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Cholangiocarcinoma (CCA) is a rare, aggressive disease with poor overall survival. In advanced cases, surgery is often not possible or fails; in addition, there is a lack of effective and specific therapies. Multidisciplinary approaches and advanced technologies have improved the knowledge of CCA molecular pathogenesis, highlighting its extreme heterogeneity and high frequency of genetic and molecular aberrations. Effective preclinical models, therefore, should be based on a comparable level of complexity. In the past years, there has been a consistent increase in the number of available CCA models. The exploitation of even more complex CCA models is rising. Examples are the use of CRISPR/Cas9 or stabilized organoids for in vitro studies, as well as patient-derived xenografts or transgenic mouse models for in vivo applications. Here, we examine the available preclinical CCA models exploited to investigate: (i) carcinogenesis processes from initiation to progression; and (ii) tools for personalized therapy and innovative therapeutic approaches, including chemotherapy and immune/targeted therapies. For each model, we describe the potential applications, highlighting both its advantages and limits.

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Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice

Cited by 82 publications

References 45 publications

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Axis inhibition protein 1 (Axin1) Deletion–Induced Hepatocarcinogenesis Requires Intact β‐Catenin but Not Notch Cascade in Mice

Evolution of the Experimental Models of Cholangiocarcinoma

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