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  • 1
    Online Resource
    Online Resource
    An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 10 ( 2019-09-21), p. 1410-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 10 ( 2019-09-21), p. 1410-
    Abstract: Background: Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver carcinogenesis. Methods: We used inducible liver-specific transgenic mouse strains to analyze the consequences of NF-κB/p65 activation mimicking chronic inflammation and subsequent p53 loss. Results: Ikk2ca driven NF-κB/p65 activation in mice results in liver fibrosis, the formation of ectopic lymphoid structures and carcinogenesis independent of p53 expression. Subsequent deletion of Trp53 led to an increased tumor formation, metastasis and a shift in tumor differentiation towards intrahepatic cholangiocarcinoma. In addition, loss of Trp53 in an inflammatory liver resulted in elevated chromosomal instability and indicated a distinct aberration pattern. Conclusions: In conclusion, activation of NF-κB/p65 mimicking chronic inflammation provokes the formation of liver carcinoma. Collateral disruption of Trp53 supports tumor progression and influences tumor differentiation and heterogeneity.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11101410
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    Remodelling and Improvements in Organoid Technology to Study Liver Carcinogenesis in a Dish
    Wiley ; 2019
    In:  Stem Cells International Vol. 2019 ( 2019-02-19), p. 1-8
    Details
    In: Stem Cells International, Wiley, Vol. 2019 ( 2019-02-19), p. 1-8
    Abstract: Primary liver cancer (PLC) is the sixth most common tumour disease and one of the leading causes of cancer-related death worldwide. The two most common types of PLC are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Diverse subgroups are described and a manifold number of gene mutations are known. Asymptomatic disease progression and limited therapeutic options are the reasons for the high mortality rate in PLC. Up to date, the multikinase inhibitors sorafenib and lenvatinib are the only FDA-approved first-line treatments for advanced HCC. One of the major drawbacks in the preclinical drug development is the lack of suitable model systems. In recent years, 3D organoid cultures were established from several organs and tumour subtypes, thereby opening new avenues in tumour research. 3D organoid cultures are used to describe the tumour diversity, for cancer modelling in a dish and for therapy responsiveness. The establishment of living biobanks and the development of next-generation matrices are promising approaches to overcome drug resistance and to improve the quality of personalised anticancer strategies for patients with PLC. In this review, we summarise the current knowledge of 3D cultures generated from healthy liver and primary liver cancer.
    Type of Medium: Online Resource
    ISSN: 1687-966X , 1687-9678
    URL: Article
    DOI: 10.1155/2019/3831213
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2573856-2
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  • 3
    Online Resource
    Online Resource
    Pancreatic cancer‐derived organoids – a disease modeling tool to predict drug response
    Wiley ; 2020
    In:  United European Gastroenterology Journal Vol. 8, No. 5 ( 2020-06), p. 594-606
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    In: United European Gastroenterology Journal, Wiley, Vol. 8, No. 5 ( 2020-06), p. 594-606
    Abstract: Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient‐derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date. Methods We conducted a feasibility study, systematically comparing head‐to‐head patient‐derived xenograft tumor (PDX) and PDX‐derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated in vivo . Patient‐derived organoids were investigated as well. Results First, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array‐based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small‐scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. In vitro predictions were successfully validated in an in vivo xenograft trial. Translational proof‐of‐concept is exemplified in a patient with PDAC receiving palliative chemotherapy. Conclusion Small‐scale drug screening in organoids appears to be a feasible, robust and easy‐to‐handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost‐efficient assay is a reasonable approach in a predictive clinical setting.
    Type of Medium: Online Resource
    ISSN: 2050-6406 , 2050-6414
    URL: Article
    DOI: 10.1177/2050640620905183
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2728585-6
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  • 4
    Online Resource
    Online Resource
    YAP Activation Drives Liver Regeneration after Cholestatic Damage Induced by Rbpj Deletion
    MDPI AG ; 2018
    In:  International Journal of Molecular Sciences Vol. 19, No. 12 ( 2018-11-29), p. 3801-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 19, No. 12 ( 2018-11-29), p. 3801-
    Abstract: Liver cholestasis is a chronic liver disease and a major health problem worldwide. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can induce ductal proliferation, hepatocyte injury and liver fibrosis. Notch signalling promotes the formation and maturation of bile duct structures. Here we investigated the liver regeneration process in the context of cholestasis induced by disruption of the Notch signalling pathway. Liver-specific deletion of recombination signal binding protein for immunoglobulin kappa j region (Rbpj), which represents a key regulator of Notch signalling, induces severe cholestasis through impaired intra-hepatic bile duct (IHBD) maturation, severe necrosis and increased lethality. Deregulation of the biliary compartment and cholestasis are associated with the change of several signalling pathways including a Kyoto Encyclopedia of Genes and Genomes (KEGG) gene set representing the Hippo pathway, further yes-associated protein (YAP) activation and upregulation of SRY (sex determining region Y)-box 9 (SOX9), which is associated with transdifferentiation of hepatocytes. SOX9 upregulation in cholestatic liver injury in vitro is independent of Notch signalling. We could comprehensively address that in vivo Rbpj depletion is followed by YAP activation, which influences the transdifferentiation of hepatocytes and thereby contributing to liver regeneration.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms19123801
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Molecular features and vulnerabilities of recurrent chordomas
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Experimental & Clinical Cancer Research Vol. 40, No. 1 ( 2021-12)
    Details
    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 40, No. 1 ( 2021-12)
    Abstract: Tumor recurrence is one of the major challenges in clinical management of chordoma. Despite R0-resection, approximately 50% of chordomas recur within ten years after initial surgery. The underlying molecular processes are poorly understood resulting in the lack of associated therapeutic options. This is not least due to the absence of appropriate cell culture models of this orphan disease. Methods The intra-personal progression model cell lines U-CH11 and U-CH11R were compared using array comparative genomic hybridization, expression arrays, RNA-seq, and immunocytochemistry. Cell line origin was confirmed by short tandem repeat analysis. Inter-personal cell culture models ( n  = 6) were examined to validate whether the new model is representative. Cell viability after HOX/PBX complex inhibition with small peptides was determined by MTS assays. Results Using whole genome microarray analyses, striking differences in gene expression between primary and recurrent chordomas were identified. These expression differences were confirmed in the world’s first intra-personal model of chordoma relapse consisting of cell lines established from a primary (U-CH11) and the corresponding recurrent tumor (U-CH11R). Array comparative genomic hybridization and RNA-sequencing analyses revealed profound genetic similarities between both cell lines pointing to transcriptomic reprogramming as a key mechanism of chordoma progression. Network analysis of the recurrence specific genes highlighted HOX/PBX signaling as a common dysregulated event. Hence, HOX/PBX complexes were used as so far unknown therapeutic targets in recurrent chordomas. Treating chordoma cell lines with the complex formation inhibiting peptide HXR9 induced cFOS mediated apoptosis in all chordoma cell lines tested. This effect was significantly stronger in cell lines established from chordoma relapses. Conclusion Clearly differing gene expression patterns and vulnerabilities to HOX/PBX complex inhibition in highly therapy resistant chordoma relapses were identified using the first intra-personal loco-regional and further inter-personal chordoma progression models. For the first time, HOX/PBX interference was used to induce cell death in chordoma and might serve as the basic concept of an upcoming targeted therapy for chordomas of all progression stages.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    URL: Article
    DOI: 10.1186/s13046-021-02037-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2430698-8
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