Genome-wide profiling of transcription factor activity in primary liver cancer using single cell ATAC sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227265 | GEO | 2023/11/08
REPOSITORIES: GEO
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Project description:Background & Aims: Combined HCC-iCCA is a rare liver tumor type and is often not well separated from HCC and iCCA. In this study, we analyzed major differences between combined HCC-iCCA and iCCA. Methods: We first characterized major differences between combined HCC-iCCA and iCCA by GSEA analysis. Consequently, we used CCl4 to induce chronic liver disease and subsequent liver carcinoma formation in mice. We forced the formation of combined HCC-iCCA through liver specific deletion of Rbpj, a key component of the Notch signaling pathway, in a Trp53 deficient background. Notch and p53 signaling pathways are involved in cellular differentiation processes and belong to the most affected pathways in liver carcinogenesis. Results: We show that combined HCC-iCCA can be separated from iCCA through differences in development related pathways, metabolism, cell to cell interaction and immune related pathways in human patients and in mice. Dysregulation of Notch signaling through a hepatocyte-specific Rbpj knockout resulted in an increased tumor burden and a high frequency of combined HCC-iCCA formation. In addition, hepatocytic loss of Rbpj forced M2 macrophage polarization and a tumor promoting environment. Conclusions: Dysregulation of Notch signaling is involved in tumor differentiation. Loss of Rbpj triggers the formation of combined HCC-iCCA which is associated by a pro-tumorigenic environment. Our study highlights the importance of dysfunctional Notch signalling through Rbpj deletion in hepatocytes. Rbpj loss affects tumor differentiation and the tumor microenvironment which can be linked to a combined HCC-iCCA phenotype seen in human patients.
2023-08-31 | GSE212095 | GEO
Project description:Background & Aims: Combined HCC/iCCA is a rare liver tumor type. We generated a transgenic mouse model (AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mouse) which developed next to HCC combined HCC/iCCA (cHCC/iCCA). We compared bilineal differentiated liver carcinoma cell lines generated from primary liver tumors of AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mice and transplanted them into C57BL/6J mice to monitor there agressiveness. We compared the geneexpression profile from those primary liver carcinoma cell lines with IFNγ treatment (pCCL-IFNγ) and without treatment (pCCL) with explanted primary carcinoma cell line (pCCL-ex). Results: Here we describe that elimination of HBs+ in pCCL by HBs/(Kb/S190-197)-specific CD8 T cells describes a potential immune escape mechanism for highly aggressive cHCC/iCCA-type liver carcinomas.
2023-05-23 | GSE215059 | GEO
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.
2022-07-12 | GSE179443 | GEO
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.
2022-06-09 | PXD032802 | Pride
Project description:Embryonic stem cells (ESCs) have the potential to yield new liver cells for regenerative medicine. However it has been challenging to generate homogeneous ESC-derived human liver populations capable of engrafting in vivo and ameliorating liver failure. To overcome this challenge, we define extrinsic signals regulating six consecutive stages of human liver development, including patterning of endoderm into foregut, liver bud specification, and segregation of hepatocyte vs. biliary fates. This knowledge enabled differentiation of human ESCs into 89% pure AFP+HNF4A+TBX3+ liver bud progenitors and subsequently, a >77% uniform ALB+ hepatocytic population. ESC-derived ALB+ human hepatocytic cells engrafted the damaged livers of Fah-/- mice, improving overall mouse survival and reducing liver damage. Interestingly, certain signals that matured hESC-derived hepatocytic cells also sustained primary adult hepatocytes in vitro for one week. Collectively we demarcate extrinsic signaling, mRNA and surface marker dynamics during human liver development, enabling the generation of engraftable liver cells from ESCs.
2018-02-20 | GSE98324 | GEO
Project description: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.
2022-08-12 | GSE201241 | GEO
Project description:Intrahepatic cholangiocarcinoma (iCCA) is characterized by its highly desmoplastic stroma. Myofibroblasts (MFs) are present both within the tumor mass (intratumoral MFs, iMFs) and at the tumor border (peritumoral MFs, pMFs). Using a spheroid-based coculture system, we show that the initial iCCA-pMF contact is growth suppressive to the tumor cells. However, prolonged iCCA-pMF interaction elicits significant tumor cell invasion and dissemination. We find that vascular cell adhesion molecule-1 (Vcam1) level is elevated in tumor cells in contact with pMFs but low in disseminated tumor cells both in vitro and in vivo. A gene regulatory network analysis of mouse and patient iCCA tumors and Vcam1 knockout (Vcam1KO) demonstrate a heavy involvement of Vcam1 in epithelial-to-mesenchymal transition. While Vcam1KO has only a limited impact on tumor cell growth in their monoculture, Vcam1KO spheroids exhibit instant dissemination and a severe growth defect when cocultured with pMFs. When transplanted into the liver, Vcam1KO iCCA cells show a similar increase in dissemination but a significant defect in establishing primary and metastatic tumors. Incomplete blocking of Vcam1 in vivo reduces the size but increase the number of metastatic lesions. Overall, our study shows a spatiotemporal regulation of iCCA growth and dissemination by pMFs in a Vcam1-dependent manner.
2023-02-22 | GSE223562 | GEO
Project description:The transcriptional cofactor yes-associated protein (YAP) functions as a proto-oncogene and a key effector of the canonical Hippo pathway. Phosphorylation at serine 127 (S127) by core Hippo kinases inhibits YAP activity, while phosphorylation at tyrosine 357 (Y357) by SRC-family kinases promotes its activation. YAP activation has been implicated in many cancers, including primary liver cancers (PLCs). Owing to the inherent plasticity of the liver, PLCs may arise from different cells of origin. However, it is unknown whether the level of YAP activation favors liver tumorigenesis from specific cells of origin or instead promotes lineage commitment in a single cell of origin across the PLC spectrum. To assess the role of YAP tyrosine phosphorylation in liver tumorigenesis, C57BL/6 mice underwent biliary transfection with the Sleeping Beauty transposon system to deliver myr-AKT and YAP S127A (YAP-S) or YAP S127A/Y357F (YAP-SY). While YAP-S mice represent an established model of intrahepatic cholangiocarcinoma (iCCA), unexpectedly, a shift in tumor phenotype to hepatocellular carcinoma (HCC) was identified in YAP-SY mice. Transcriptome and pathway analysis revealed differential activation of cytokines and growth factors (e.g., TGFB1, TNF, IL1B, IL4, and INFG) and transcription factors (e.g., STAT3, PGR, AHR, STAT1, and NFKB) associated with this phenotypic switch. To determine the cell of origin, tumors were generated in lineage tracing mice (ROSA26mT/mG mice treated with AAV8-TBG-Cre), which demonstrated that HCC originated from hepatocytes and iCCA from cholangiocytes in the biliary transfection model. Finally, two tumor-derived cell lines with YAP-SY and constitutive AKT expression were isolated, representing a novel, transplantable murine syngeneic model with mixed features of HCC and iCCA.
2025-12-31 | GSE297845 | GEO
Project description:Introduction: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a mixed-type tumor of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which is classified into classical type (i.e., c-CHC) and intermediate cell type (i.e., i-CHC). c-CHC harbors both HCC and iCCA cells, whereas i-CHC is comprised of intermediate cell types lacking classical regions of HCC or iCCA cells. Notwithstanding the unique pathological feature of i-CHC, its molecular characteristics is not fully elucidated yet. Methods: To obtain molecular insights on the i-CHC, RNA-sequencing (RNA-Seq) and whole genome sequencing (WGS) profiling were performed on the tissues of i-CHC, HCC, and iCCA, respectively. Results: i-CHC showed unique transcriptomic features differing from HCC and iCCA, showing higher expression of Notch signaling and frequent splicing events of intron-retention (IR). Noticeably, we found that i-CHC had DNA-copy number loss and concomitant transcriptional suppression of METTL16, which may contribute to the aggressive progression of i-CHC via Notch activation. Conclusions: We suggest that i-CHC had unique transcriptomic features, providing new insights into the pathobiology of i-CHC.
2024-08-14 | GSE241466 | GEO
Project description:Background We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites. Methods For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain. Results The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition. Conclusions The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.
2024-11-20 | GSE252130 | GEO