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Modeling Pathogenesis of Primary Liver Cancer in Lineage Specific Cell Types

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE41312 | GEO | 2013/10/01

SECONDARY ACCESSION(S): PRJNA176489

REPOSITORIES: GEO

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Project description:Recent studies suggested that embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) may represent different pluripotent states as defined by gene expression profiles and differentiation potential. Here we addressed a contribution of a lineage stage-specific donor cell memory in modulating the functional properties of iPSCs. iPSCs were generated from hepatic lineage cells at an early (hepatoblast-derived, HB-iPSCs) and end stage (adult hepatocyte, AH-iPSCs) of hepatocyte differentiation as well as from mouse fetal fibroblasts (MEF-iPSCs) using a lentiviral vector encoding four pluripotency-inducing factors Oct4, Sox2, Klf4, and c-Myc. All resulting iPS cell lines acquired iPSCs phenotype as judged by the accepted criteria including morphology, expression of pluripotency markers, silencing of transducing factors, capacity of multilineage differentiation in teratoma assay and normal diploid karyotype. However, hepatoblasts were more susceptible to reprogramming than either AH or MEF, and HB-iPSCs were more efficient in directed differentiation towards hepatocytic lineage as compared to AH-iPSCs, MEF-iPSCs or mESCs. Extensive comparative transcriptome analyses of the early passage iPSCs, donor cells and mESCs revealed that despite global similarities in gene expression patterns between generated iPSCs and mESCs, HB-iPSCs retained a transcriptional memory (7 up- and 20 down-regulated genes) typical of the original cells. Continuous passaging of HB-iPSCs abolished most of these differences including a superior capacity of hepatic re-differentiation. These results suggest that retention of lineage stage-specific donor memory in iPSCs may facilitate differentiation into donor cell type. The identified gene set may be helpful to improve hepatic differentiation for therapeutic application in liver disease modeling. A total of 200 ng RNA from four independent biological replicates of MACS-sorted mESC and iPSC were linearly amplified according to manufactures’ specification (Ambion, Austin, Tx,). For in vitro transcription (IVT), reactions were incubated for 16 h at 37ºC. The efficiency of the single round amplification was measured by NanoDrop (ND1000, Thermo Scientific). Hybridization, washing, detection (Cy3-streptavidin, Amersham Biosciences, GE Healthcare), and scanning were performed on an illumina iScan system (Illumina) using reagents and following protocols supplied by the manufacturer. The biotinylated cRNA (750 ng/sample) was hybridized on Sentrix beadchips human Ref-8v3 for 18 h at 58ºC while rocking (5 rpm).

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Modeling Pathogenesis of Primary Liver Cancer in Lineage Specific Cell Types

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