Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Fouassier, Laura; Marzioni, Marco; Afonso, Marta B.; Dooley, Steven; Gaston, Kevin; Giannelli, Gianluigi; Rodrigues, Cecília M. P.; Lozano, Elisa; Mancarella, Serena; Segatto, Oreste; Vaquero, Javier; Marin, José J.G.; Coulouarn, Cédric

doi:10.1111/liv.14102

Cited by 65 publications

(61 citation statements)

References 212 publications

(451 reference statements)

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“…Promising new agents in early clinical development for the treatment of CCA include compounds that target the JAK/STAT pathway, the Wnt/β-catenin signaling and the Hedgehog signaling (HH) pathways. JAK/STAT pathway activation is directly involved in several cellular process characteristics of cancer cells, including cell growth, proliferation, and apoptosis [80][81][82].…”

Section: Other Target Agents In Early Clinical Developmentmentioning

confidence: 99%

“…Multiple WNT pathway inhibitors are currently under clinical development (see Table 2). The activation of the hedgehog pathway results in chronic hepatic inflammation, fibrosis, cholangiopathies and in the development of CCA [80,83]. In cancer specimens of CCA, the expression of Hedgehog pathway components have been associated with disease stage and prognosis [85].…”

Section: Other Target Agents In Early Clinical Developmentmentioning

confidence: 99%

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New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

Massironi

Pilla

Elvevi

et al. 2020

Cells

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Cholangiocarcinoma (CCA) represents a disease entity that comprises a heterogeneous group of biliary malignant neoplasms, with variable clinical presentation and severity. It may be classified according to its anatomical location and distinguished in intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), each subtype implying distinct epidemiology, biology, prognosis, and strategy for clinical management. Its incidence has increased globally over the past few decades, and its mortality rate remains high due to both its biological aggressiveness and resistance to medical therapy. Surgery is the only potentially curative treatment and is the standard approach for resectable CCA; however, more than half of the patients have locally advanced or metastatic disease at presentation. For patients with unresectable CCA, the available systemic therapies are of limited effectiveness. However, the advances of the comprehension of the complex molecular landscape of CCA and its tumor microenvironment could provide new keys to better understand the pathogenesis, the mechanisms of resistance and ultimately to identify promising new therapeutic targets. Recently, clinical trials targeting isocitrate dehydrogenase (IDH)-1 mutations and fibroblast growth factor receptor (FGFR)-2 fusions, as well as immunotherapy showed promising results. All these new and emerging therapeutic options are herein discussed.

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Section: Other Target Agents In Early Clinical Developmentmentioning

confidence: 99%

Section: Other Target Agents In Early Clinical Developmentmentioning

confidence: 99%

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

Massironi

Pilla

Elvevi

et al. 2020

Cells

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“…To determine whether DLL4, VEGFA, and MMP13 are NOTCH direct transcriptional targets, we performed an in silico prediction of the binding sites for RPBJ, the transcriptional co-activator of NOTCH [7], on DLL4, VEGFA, and MMP13 gene promoters using the EPDnew database [21]. Noticeably, we identified several putative binding sites for RPBJ on DLL4, VEGFA and MMP13 gene promoter regions (P < 0.01; Supplementary Fig.…”

Section: Validation Of Dll4 Vegfa and Mmp13 Genes As Direct Notch Tmentioning

confidence: 99%

“…Both receptors and ligands are cell surface transmembrane proteins, and therefore, Notch activation is initiated by direct cell-cell interactions. Once generated, NICD enters the cell nucleus and binds RBPJ, which acts as a transcriptional co-activator, by inducing important effects on cell fate, reprogramming, and growth [7]. Thus, it is not surprising that the gamma-secretase inhibitor (GSI) LY3039478, orally administered, is currently under investigation in clinical trials for different gastrointestinal advanced malignancies (https://clinicaltrials.…”

Section: Introductionmentioning

confidence: 99%

Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis

et al. 2020

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Intrahepatic cholangiocarcinoma (iCCA) is a deadly disease with rising incidence and few treatment options. An altered expression and/or activation of NOTCH1-3 receptors has been shown to play a role in iCCA development and progression. In this study, we established a new CCA patient-derived xenograft model, which was validated by immunohistochemistry and transcriptomic analysis. The effects of Notch pathway suppression by the Crenigacestat (LY3039478)-specific inhibitor were evaluated in human iCCA cell lines and the PDX model. In vitro, LY3039478 significantly reduced Notch pathway components, including NICD1 and HES1, but not the other Notch receptors, in a panel of five different iCCA cell lines. In the PDX model, LY3039478 significantly inhibited the Notch pathway and tumor growth to the same extent as gemcitabine. Furthermore, gene expression analysis of iCCA mouse tissues treated with LY3039478 revealed a downregulation of VEGFA, HES1, and MMP13 genes. In the same tissues, DLL4 and CD31 co-localized, and their expression was significantly inhibited in the treated mice, as it happened in the case of MMP13. In an in vitro angiogenesis model, LY3039478 inhibited vessel formation, which was restored by the addition of MMP13. Finally, RNA-sequencing expression data of iCCA patients and matched surrounding normal liver tissues downloaded from the GEO database demonstrated that NOTCH1, HES1, MMP13, DLL4, and VEGFA genes were significantly upregulated in tumors compared with adjacent nontumorous tissues. These data were confirmed by our group, using an independent cohort of iCCA specimens. Conclusion: We have developed and validated a new iCCA PDX model to test in vivo the activity of LY3039478, demonstrating its inhibitory role in Notch-dependent angiogenesis. Thus, the present data provide new knowledge on Notch signaling in iCCA, and support the inhibition of the Notch cascade as a promising strategy for the treatment of this disease.

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“…1 A range of perturbed signaling pathways and genomic alterations was found to be associated with late-stage cholangiocarcinoma, but there is still limited knowledge about how such pathways and mutations evolve throughout tumorigenesis. [2][3][4][5][6][7][8] Moreover, our understanding of this process is further complicated by the observation that iCCA can arise from several cell types, namely cholangiocytes, hepatocytes, progenitor cells and peribiliary glands. [9][10][11][12][13][14][15][16] Histopathological studies identified two subtypes of iCCA in humans.…”

Section: Introductionmentioning

confidence: 99%

A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression

Di-Luoffo

Pirenne

Saandi

et al. 2019

Preprint

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Background & AimsAlthough earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) is necessary to improve therapy, there is still limited information available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression towards invasive tumor using experimental models that faithfully recapitulate human tumorigenesis.MethodsWe generated a new mouse model which combines cholangiocyte-specific expression of KrasG12D with 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines.ResultsMice expressing KrasG12D in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs) and eventually iCCAs. The histology of mouse and human IPNBs were highly similar, and mouse iCCAs displayed histological characteristics of human mucin-producing large duct type iCCA. Signaling pathways activated in human iCCA were activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We provide evidence that a gene cascade which comprises KRASG12D, SRY-related HMG box transcription factor 17 (SOX17) and Tensin 4 (TNS4), and which is activated by epidermal growth factor, promotes tumor progression.ConclusionsWe developed a novel mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade promoting tumor progression.

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Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Cited by 65 publications

References 212 publications

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis

A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression

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