Integrative Analysis Defines Distinct Prognostic Subgroups of Intrahepatic Cholangiocarcinoma
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ABSTRACT: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. It is defined by cholangiocytic differentiation and has poor prognosis. Recently, epigenetic processes have been shown to play an important role in cholangiocarcinogenesis. We performed an integrative analysis on 52 iCCAs using both genetic and epigenetic data with a specific focus on DNA methylation components. We identified four major iCCA subgroups with widespread genomic and epigenomic differences and prognostic implications. Furthermore, our data suggest differences in the cell-of-origin of the iCCA subtypes.
Project description:We have profiled by RNA-sequencing healthy livers and 4 distinct murine intrahepatic cholangiocarcinoma (iCCA) models to compare their molecular profile to the identified human STIM clusters of iCCA. Results: Comparative analysis indicated high molecular similarity between the KRAS/p19 model and the human Inflammatory stroma cluster while the other models resembled the Hepatic stem-like cluster.
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome sequencing analyses we have discovered a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%).
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome sequencing analyses we have discovered a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Methods: mRNA and gDNA were exctracted from fresh frozen tumor tissues and corresponding normal tissue (n=8 pairs) from patients with iCCA who underwent surgical resection. RNA-seq was performed using Illumina HiSeq 2500 System with 100 nucleotide single-end reads. One sample and its paired non-tumoral tissue were eliminated from the subsequent analysis because of bad RNa quality. The same 8 paired tumors were also analyzed by whole-exome seq. Submitter confirms there are no patient privacy concerns with these data. This dataset is part of the TransQST collection.
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.
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.
Project description:Cholangiocarcinoma (CCA) is a deadly tumour lacking effective therapies. Clinically-relevant experimental models and analysis of human samples represent the cornerstone of mechanistic cancer research. Thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats encompasses key histological and molecular features of human iCCA. Molecular studies in bile may capture carcinogenic alterations and therapeutic vulnerabilities in CCA. We performed bile proteomic and metabolomic analyses in this model leading us to identify unrecognized mechanisms relevant to human iCCA.
Project description:Background and aims: Primary liver cancers (LCs), including HCC and intrahepatic cholangiocarcinoma (iCCA), are derived from a common developmental lineage, conferring a molecular spectrum between them. To elucidate the molecular spectrum, we performed an integrative analysis of transcriptome profiles associated with patients' radiopathologic features. Approach and results: We identified four LC subtypes (LC1-LC4) from RNA-sequencing profiles, revealing intermediate subtypes between HCC and iCCA. LC1 is a typical HCC characterized by active bile acid metabolism, telomerase reverse transcriptase promoter mutations, and high uptake of gadoxetic acid in MRI. LC2 is an iCCA-like HCC characterized by expression of the progenitor cell-like trait, tumor protein p53 mutations, and rim arterial-phase hyperenhancement in MRI. LC3 is an HCC-like iCCA, mainly small duct (SD) type, associated with HCC-related etiologic factors. LC4 is further subclassified into LC4-SD and LC4-large duct iCCAs according to the pathological features, which exhibited distinct genetic variations (e.g., KRAS , isocitrate dehydrogenase 1/2 mutation, and FGF receptor 2 fusion), stromal type, and prognostic outcomes. Conclusions: Our integrated view of the molecular spectrum of LCs can identify subtypes associated with transcriptomic, genomic, and radiopathologic features, providing mechanistic insights into heterogeneous LC progression.
Project description:Interferon-α2b (IFN-α2b) is a highly active cytokine protein that belongs to the interferon-α (IFN-α) family. As a pleiotropic cytokine, IFN-α2b has beneficial antiviral, antitumour, antiparasitic, and immunomodulatory activities. In vivo and in vitro, IFN-α2b can activate the JAK-STAT pathway (also known as IFN-I pathway) and function by inducing the transcription of downstream IFN-stimulated genes (ISGs).To identify the ISGs in intrahepatic cholangiocarcinoma (ICCA) cells and evaluate the therapeutic value of IFN-α2b, ICCA cells were treated with recombinant IFN-α2b protein. Total RNA samples were extracted and used for RNA-seq. Certain ISGs (e.g., MXs, IFITs, OASs) were found to be significantly upregulated upon IFN-α2b treatment.
Project description:Abnormal distribution of histone modifications has been confirmed to influence the development and progression of neoplastic diseases. Methylation modifications of histone H3 include H3K9me3, H3K27me3 and H3K4me3. Acetylation modifications of histone H3 include H3K9ac and H3K27ac. Among these modifications in the promoter region, H3K9me3 and H3K27me3 serve as inhibiting factors for transcription, while H3K4me3, H3K9ac and H3K27ac are important promoting factors for transcription. To make sure the distribution of these histone modifications in intrahepatic cholangiocarcinoma (ICCA) cells, CUT & Tag was performed. We found that these modifications were located in the promoter or non-promoter regions (e.g., intergenic, exon and intron regions) of key tumor-associated genes, indicating the potential role of chromatin remodeling complexes in ICCA diagnosis and treatment.