Effect of Crenigacestat treatment in xenograft model of HUCCT1 intrahepatic cholangiocarcinoma
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PROVIDER: PRJNA630916 | ENA |
REPOSITORIES: ENA
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Project description:Intrahepatic Cholangiocarcinoma (iCCA) is a difficult type of cancer to diagnose, extremely aggressive and resistant to therapeutic options with an increased incidence and mortality over time. The overexpression of Notch pathway is implicated in iCCA to create an ecosystem that drives the tumor aggressiveness. Specifically, Notch1 is overexpressed in iCCA tissue of patients, playing an important role on tumor growth. Our purpose was to investigate the effectiveness of Crenigacestat in in vivo experiments, using Hucct1 injected in CD1 mice to generate an iCCA xenograft mouse model. In the present study, in order to explore modulated factors and genes by treatment we performed a transcriptomic analysis validated by Western Blotting and qRT-PCR on iCCA tumor masses of xenograft mice. Our results indicate that the treatment significantly inhibited Notch1 and HES1 genes and proteins triggering a strong immune response. Nevertheless, moderate fibrosis was shown in this model which may have hindered response to therapy to promote tumor progression. We used microarray technology to understand the molecular mechanisms affected by Crenigacestat in HUCCT1 xenograft model of intraepatic cholangiocarcinoma.
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Project description:Molecular mechanisms responsible for the poor prognosis in patients with intrahepatic cholangiocarcinoma (CCA) are still unknown, however, the stem cell marker cluster differentiation 90 (CD90), has been reported to be associated with a more aggressive cancer phenotype. In this scenario, TGFβ1 signaling pathway likely has a role as master gene regulator. Aim of the study is to investigate the role of CD90 in iCCA aggressiveness. The molecular profile of HuCCT1/CD90+ and HuCCT1/CD90- cells was obtained through transcriptomic analysis (NGS). Bioinformatic data were confirmed in both cell lines by qRT-PCR and western blot. Cells were treated with Gemcitabine in monotherapy or in combination with Galunisertib, a selective TGFβRI inhibitor in 2D and 3D models. HuCCT1 CD90 positive cells are more proliferative, less migratory, and resistant to Gemcitabine treatment. Next, HuCCT1/CD90+ express lower levels of TGFβ1 compared to /CD90- cell lines. Finally, HuCCT1/CD90+ are resistant to Gemcitabine, while the combination of both Gemcitabine and Galunisertib displays a synergistic effect on HuCCT1/CD90+ cell proliferation. These results underline that CD90 inducing Gemcitabine resistance can be overcome by adding a TGFβ1 inhibitor such as Galunisertib, thereby moving further toward a precision medicine approach in patients with iCCA.
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Project description:The aim of the study was to characterize the transcriptional profile of cholangiocarcinoma cell line HuCCT1 after transfection with a plasmid encodind the long isoform of CASC15 (Gene ID: 401237 ; RNA sequence: NR_015410.1).
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Project description:The YAP pathway in regulating organ size by integrating external signals to control the expression of genes involved in cell proliferation. YAP is known to be involved in tumorigenesis in several tissues, yet its role in cholangiocarcinoma is not established We used microarrays to assess the role of YAP pathway in cholangiocarcinoma either by overexpressing a constitutively active YAP1 mutant, or by downregulating YAP1 expression using shRNA HuCCT1 cells where transfected with either an empty vector or a vector overexpressing the constitutively active YAP1 S127A; cells were harvested, RNA was collected and analyzed using microarray
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Project description:Trichostatin A (TSA) is a commonly used antifungal drug characterized by inhibiting the activity of histone deacetylases (HDACs). As an antineoplastic agent, the pharmacological actions of TSA includes: 1. Inhibiting the proliferation of tumor cells directly; 2. Promoting the antitumor effect of immune cells; 3. Enhancing the efficacy of other antitumor drugs. The efficacy of TSA in the treatment of intrahepatic cholangiocarcinoma (ICCA) is still unknown and needs further verification. Therefore, in this study, ICCA cell line HUCCT1 was treated by TSA. The total RNA samples were used for transcriptome analysis to find the potential target of HDACs.
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Project description:The YAP pathway in regulating organ size by integrating external signals to control the expression of genes involved in cell proliferation. YAP is known to be involved in tumorigenesis in several tissues, yet its role in cholangiocarcinoma is not established We used microarrays to assess the role of YAP pathway in cholangiocarcinoma either by overexpressing a constitutively active YAP1 mutant, or by downregulating YAP1 expression using shRNA HuCCT1 cells where transfected with either an empty vector or a vector overexpressing the constitutively active YAP1 S127A; cells were harvested, RNA was collected and analyzed using microarray
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Project description:Intrahepatic cholangiocarcinoma (ICC) is a lethal cancer arising from intrahepatic bile ducts in the liver. In the intraductal growth (IDG) type, also referred to as intraductal papillary neoplasm of the bile duct (IPNB), a rare subtype of ICC, cancer cells originating within the bile duct usually invade and infiltrate the nearby liver tissues, resulting in local invasion. IPNB can serve as a good disease model to study the mechanism of local invasion, which is the earliest step of metastasis. Here, we aimed to identify the genes associated with local invasion by comparing the somatic mutations of the matched IPNB tissues with and without local invasion from a set of 11 patients using the Ion AmpliSeq Comprehensive Cancer Panel. Somatic mutation profiling analysis identified RNF213 as a potential candidate gene associated with local invasion in ICC patients. We established stable RNF213-knockdown and shControl cholangiocarcinoma (CCA) cell lines (HuCCT1, YSCCC, and KKU-100). Next, the expression profiling of the RNF213-knockdown and shContol CCA cell lines was analyzed by RNA sequencing.
2024-07-24 | GSE235891 | GEO
Project description:Intrahepatic Cholangiocarcinoma (iCCA) is a deadly disease with rising incidence and few treatment options. Recently, aberrant Notch signaling was reported in iCCA carcinogenesis. Specifically, altered expression and/or activation of the receptors Notch1/2 suggests a role for Notch pathway overactivation during iCCA formation and progression. In this study, we examined the effects of Notch inhibition by γ-secretase inhibitor, LY3039478 in human iCCA cell lines and in an excellent patient derived-xenograft (PDX) model. Expression of several Notch pathway components, including NICD, Hes1, and DLL4, were reduced after GSI treatment. Moreover, LY3039478 inhibits cell migration and invasion while in GSI-treated mice, tumor growth was delayed compared to vehicle and chemotherapy. These results support the notion that Notch inhibition by GSI may reduce in vivo tumorigenesis. In addition, GSI reduces in PDX model VEGFA and MMP13 involved in capillary tube formation and tumor progression. Here, we therefore show a link between the efficacy of Notch inhibition and the tumor microenvironment through LY3039478 that slows tumor progression compared to control mice blocking angiogenesis via MMP13 downregulation. We used microarray technology to understand the molecular mechanisms affected by LY3039478. Cholangiocarcinoma PDX model was employed in this analysis.
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Project description:The YAP pathway in regulating organ size by integrating external signals to control the expression of genes involved in cell proliferation. YAP is known to be involved in tumorigenesis in several tissues, yet its role in cholangiocarcinoma is not established We used microarrays to assess the role of YAP pathway in cholangiocarcinoma either by overexpressing a constitutively active YAP1 mutant, or by downregulating YAP1 expression using shRNA HuCCT1 cells where transfected with either a control scrambled shRNA or a shRNA targeting YAP1; cells were harvested, RNA was collected and analyzed using microarray
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