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Myc regulates the lineage commitment of transformed hepatocytes during liver tumorigenesis (ATAC-Seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE156743 | GEO | 2023/07/24

REPOSITORIES: GEO

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Myc regulates the lineage commitment of transformed hepatocytes during liver tumorigenesis (RNA-Seq)

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

Transcriptomic signature of hepatocellular carcinoma and intrahepatic cholangiocarcinoma derived from oncogenically transformed murine hepatocytes

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

Transcriptomic signature of hepatocellular carcinoma and intrahepatic cholangiocarcinoma derived from oncogenically transformed murine hepatocytes after stable knock-down of Tbx3 or Prdm5

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Organoids derived from directly reprogrammed human hepatocytes for modeling liver cancer initiation

Project description:Hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC) are two main forms liver cancers with poor prognosis. Models for studying HCC and ICC development using human liver cells are urgently needed. Organoids serve as in vitro models for cancer studies as it recapitulates in vivo structures and microenvironment of solid tumors. Herein, we established liver cancer organoid models by introducing specific mutations into human induced hepatocyte (hiHep)-derived organoids. c-MYC and hRASG12V overexpression in hiHep organoids with repressed p53 activation by large T led to distinct HCC and ICC signatures. With these oncogenic mutations, the neoplastic hiHep organoids formed cancerous structures and possessed cancer-specific hallmarks. Comprehensive transcriptional analysis of liver cancer organoids revealed genes and pathways with disease-stage-specific alterations. Notably, with RAS mutations, hiHep organoids acquired biliary trans-differentiation, and showed a process of conversion from hepatocytes to ICC. To sum up, we have established a useful and convenient in vitro human organoid systems modeling liver cancer development.

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RNAseq of pancreatas from KRasG12D/RosaMycER+/- or KRasG12D/RosaMycER+/+ treated with Tamoxifen for 12h

Project description:Experiment designed to study the effect of 1 or 2 copies of deregulated myc on transcriptional profile during pancreatic cancer progression. In the KRasG12D/RosaMycER mouse model KRas and MycER are expressed exclusively in the pancreas, but MycER activity depends on Tamoxifen presence. RNAseq was preformed on pancreatas from KRasG12D/RosaMycER+/- or KRasG12D/RosaMycER+/+ mice treated 12 hours with Tamoxifen.

2022-06-08 | E-MTAB-10807 | biostudies-arrayexpress

Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [scATAC-seq]

Project description:Oncogenes are highly specific in the cells they can transform, although the molecular basis for this is poorly understood. Inflammation often promotes tumorigenesis, and in the pancreas it promotes cellular plasticity and accelerates Kras-driven neoplasia. We demonstrate that plasticity is coupled to the emergence of transient progenitor cells that are readily transformed by KrasG12D. The progenitor state is linked to coordinate upregulation of proliferation genes through chromatin opening at nearby lineage-specific enhancers. Mutant Kras taps into this program by co-opting the normally transient enhancer elements, making them permanent and Kras-dependent in cancer. Mechanistically, co-option occurs through cooperation of Kras-driven transcription factors with the existing landscape of pancreatic lineage transcription factors, which are recruited to play a central role in driving the mutant Kras-dependent transcriptional program. These observations suggest that proliferation is controlled by tissue-specific enhancer networks that are tapped into by oncogenes, helping explain the lineage specificity of cancer drivers.

2020-07-11 | GSE147726 | GEO

Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [RNA-seq]

2020-07-11 | GSE134235 | GEO

Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [ChIP-seq]

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Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [ATAC-seq]

2020-07-11 | GSE134230 | GEO

Modeling Pathogenesis of Primary Liver Cancer in Lineage Specific Cell Types

Project description:Classification of human liver cancer into biologically distinct subgroups suggests origin from different hepatic lineage cells. To clarify contribution of lineage stage in liver oncogenesis, we transduced H-Ras and SV40LT into hepatic progenitor cells (HPC), hepatoblasts (HB) and terminally differentiated adult hepatocytes (AH). Regardless of origin, all transformed cell types acquired common cancer stem cell characteristics in vitro and in vivo. However, expression analysis distinguished tumors of different cellular origin underscoring the contribution of lineage/stage-dependent genetic changes in malignant transformation. Notably, AH-derived tumors showed specific enrichment of c-Myc target genes. These data establish that any hepatic lineage cell can be a target for transformation and acquire common cancer stem cell traits via activation of diverse cell type specific pathways. Profiling of individual tumors derived by Ras/SV40 transformation of hepatic progenitor cell (oval cells), hepatoblasts (fetal) and adult hepatocytes

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