Organoids derived from directly reprogrammed human hepatocytes for modeling liver cancer initiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE115853 | GEO | 2019/05/20
REPOSITORIES: GEO
Similar Datasets
Project description:Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and therapy response. Yet, molecular actors and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here, we report that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumourigenesis. While a necroptosis associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes harbouring identical oncogenic drivers give rise to HCC if surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of murine HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage commitment factors, a function conserved in humans. Together, our study provides unprecedented insights into lineage commitment in liver tumourigenesis and explains molecularly why common liver damaging risk factors can either lead to HCC or ICC.
2018-06-28 | GSE112615 | GEO
Project description:Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and therapy response. Yet, molecular actors and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here, we report that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumourigenesis. While a necroptosis associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes harbouring identical oncogenic drivers give rise to HCC if surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of murine HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage commitment factors, a function conserved in humans. Together, our study provides unprecedented insights into lineage commitment in liver tumourigenesis and explains molecularly why common liver damaging risk factors can either lead to HCC or ICC.
2018-06-29 | GSE112616 | GEO
Project description:As genomic analysis technology has advanced, it has become possible to sub-classify intrahepatic cholangiocarcinoma (ICC) at the histological or molecular level. However, there are no truly representative models of ICC subtypes for use in studying developmental differences, carcinogenesis, and personalized drug response. Here, we sought to verify recent suggested two subgroup of ICC in organoids model, compare the characteristics between LD and SD type of ICC, and find the type-specific gene expression profile and targetable pathway as a therapeutic target. ICC organoids from 16 patients pathologically diagnosed with cholangiocarcinoma were prepared according to a previously established organoid culture protocol. ICC patients were subclassified into small-duct (SD) type and large-duct (LD) type according to histological characteristics and S100P, N-cadherin, and CD56 expression. ICC organoids were successfully established within one month and exhibited a morphology similar to that of their matching primary cancer. LD- and SD-type organoids exhibited histologic phenotypes and staining patterns characteristic of the corresponding ICC subtypes. ICC organoids showed high concordance of somatic mutations with primary tumors. Unsupervised principal component analysis clustering effectively separated each type of ICC. Differential gene expression revealed significant enrichment on KRAS, TGFβ and ERBB2 signaling pathways in LD-type compared with SD-type ICC (P<0.05). Gene set enrichment analysis further demonstrated that the cholangiocarcinoma class 2 signature, defined by Andersen et al., was significantly enriched in the LD-type (enrichment score=2.19, P<0.001). A protein-protein interaction network analysis identified ZNF217 as a significant hub protein (odds ratio=4.96, P=0.0105). We successfully performed prospective modeling of histological subtype specification using patient-derived ICC organoids. Moreover, gene expression profiling of ICC organoids enabled identification of type-specific targetable pathways.
2022-11-26 | GSE215997 | GEO
Project description:<p>Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We performed targeted sequencing of Thai ICC and HCC among the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) cohort using the OncoVar platform.</p>
| phs001199 | dbGaP
Project description:Current in vitro models of primary liver cancer fail to recapitulate the key characteristics of original cancer. We construct the long-term organoids culture from tumor tissue of primary liver cancer (PLC) patients with varieties of subtypes. PLC organoids retain the histopathological features of originating tumor. Organoids transplantation proved that the tumorogenic potential and histological characteristics of PLC organoids are well preserved in vivo. PLC organoids are amenable for preclinical drug screening test and identification of mammalian target of rapamycin (mTOR) inhibitor compound as a potential therapeutic treatment for PLC. Besides, we also establish sorafenib-resistant hepatocellular carcinoma (HCC) organoids to clarify the mechanisms that drive resistance. In conclusion, PLC organoids models provide a platform for drug development for PLC and theoretical basis for HCC resistance.
2023-02-22 | GSE182593 | GEO
Project description:The two oncogenes Myc and Kras cooperate to drive tumorigenesis and tumor suppressive pathways, to regulate the tumor microenvironment and to respond to immuno-therapies in different types of cancer. However, the interactions between Myc and Kras in cancer plasticity remain largely unknown. Primary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), two tumor subtypes which are morphologically and clinically different, and cell intrinsic molecular mechanisms that lead to the onset of HCC or ICC remain elusive. Here using a mouse model of KrasG12D-driven ICC we show that Myc overexpression switches the tumorigenesis towards HCC. Lineage tracing experiments showed that this switch occurred in KrasG12D transformed hepatocyte fated to develop into ICC. Since cell fate decisions during lineage differentiation are coordinately regulated by transcriptional and epigenetic changes, we took advantage of transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiling to analyze hepatocytes transformed either with KrasG12D only or with KrasG12D and Myc. We identified Foxa1, Foxa2 and Ets1 as the major transcription factors responsible of the lineage commitment of transformed hepatocytes towards ICC or HCC, a function that is conserved also in humans. Altogether, our study describes an unanticipated cell intrinsic mechanism of lineage determination during the development of primary liver cancer orchestrated by the oncogene Myc.
2023-07-24 | GSE156744 | GEO
Project description:The two oncogenes Myc and Kras cooperate to drive tumorigenesis and tumor suppressive pathways, to regulate the tumor microenvironment and to respond to immuno-therapies in different types of cancer. However, the interactions between Myc and Kras in cancer plasticity remain largely unknown. Primary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), two tumor subtypes which are morphologically and clinically different, and cell intrinsic molecular mechanisms that lead to the onset of HCC or ICC remain elusive. Here using a mouse model of KrasG12D-driven ICC we show that Myc overexpression switches the tumorigenesis towards HCC. Lineage tracing experiments showed that this switch occurred in KrasG12D transformed hepatocyte fated to develop into ICC. Since cell fate decisions during lineage differentiation are coordinately regulated by transcriptional and epigenetic changes, we took advantage of transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiling to analyze hepatocytes transformed either with KrasG12D only or with KrasG12D and Myc. We identified Foxa1, Foxa2 and Ets1 as the major transcription factors responsible of the lineage commitment of transformed hepatocytes towards ICC or HCC, a function that is conserved also in humans. Altogether, our study describes an unanticipated cell intrinsic mechanism of lineage determination during the development of primary liver cancer orchestrated by the oncogene Myc.
2023-07-24 | GSE156743 | GEO
Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations (CNV) were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. CNV-based clustering was able to further refine these molecular groups. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. Gene-expression profiling was performed using formalin-fixed, paraffin-embedded intrahepatic cholangiocarcinoma tissues obtained at the time of surgical resection.
2013-01-24 | E-GEOD-32225 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations (CNV) were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. CNV-based clustering was able to further refine these molecular groups. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. DNA copy number profiling was performed using formalin-fixed, paraffin-embedded intrahepatic cholangiocarcinoma tissues obtained at the time of surgical resection.
2013-01-24 | E-GEOD-33326 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations (CNV) were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. CNV-based clustering was able to further refine these molecular groups. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-01-24 | E-GEOD-33327 | biostudies-arrayexpress