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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:Hepatocellular carcinoma highly occurs in chronic hepatitis livers, where hepatocyte apoptosis is frequently detected. Apoptosis is a mechanism that eliminates mutated cells. Hepatocyte apoptosis induces compensatory liver regeneration, which is believed to contribute to tumor formation. Hepatocyte-specific Mcl-1 knockout mice (Mcl-1Δhep mice) developed persistent hepatocyte apoptosis and compensatory liver regeneration with increased oxidative stress in adulthood but had not yet developed hepatocyte apoptosis at the age of 2 weeks. When diethylnitrosamine (DEN) was administered to 2-week-old Mcl-1Δhep mice, multiple liver tumors were formed at 4 months, while wild-type mice did not develop any tumors. These tumors contained the B-Raf V637E mutation, indicating that DEN-initiated tumorigenesis was promoted by persistent hepatocyte apoptosis. When N-acetyl-L-cysteine was given from 6 weeks of age, DEN-administered Mcl-1Δhep mice had reduced oxidative stress and suppressed tumorigenesis in the liver but showed no changes in hepatocyte apoptosis or proliferation. In conclusion, enhanced tumor formation from DEN-transformed hepatocytes by persistent hepatocyte apoptosis is mediated by increased oxidative stress, independent of compensatory liver regeneration. For patients with livers harboring transformed cells, the control of oxidative stress may suppress hepatocarcinogenesis based on chronic liver injury.
| S-EPMC7873060 | biostudies-literature
Project description:Despite recent insights gained from the effects of targeted deletion of the Finkel-Biskis-Jinkins osteosarcoma oncogene (c-fos), Spleen focus-forming virus (SFFV) proviral integration 1 (PU.1), microphthalmia-associated transcription factor, NF-?B, and nuclear factor of activated cells cytoplasmic 1 (NFATc1) transcription factor genes, the mechanism underlying transcription factors specifying osteoclast (OC) lineage commitment from monocyte/macrophage remains unclear. To characterize the mechanism by which transcription factors regulate OC lineage commitment, we mapped the critical cis-regulatory element in the promoter of cathepsin K (Ctsk), which is expressed specifically in OCs, and found that CCAAT/enhancer binding protein ? (C/EBP?) is the critical cis-regulatory element binding protein. Our results indicate that C/EBP? is highly expressed in pre- OCs and OCs. The combined presence of macrophage colony-stimulating factor and receptor activator of NF-?B ligand significantly induces high C/EBP? expression. Furthermore, C/EBP?(-/-) newborn mice exhibited impaired osteoclastogenesis, and a severe osteopetrotic phenotype, but unaffected monocyte/macrophage development. Impaired osteoclastogenesis of C/EBP?(-/-) mouse bone marrow cells can be rescued by c-fos overexpression. Ectopic expression of C/EBP? in mouse bone marrow cells and monocyte/macrophage cells, in the absence of receptor activator of NF-?B ligand, induces expression of receptor activator of NF-?B, c-fos, Nfatc1, and Ctsk, and it reprograms monocyte/macrophage cells to OC-like cells. Our results demonstrate that C/EBP? directly up-regulates c-fos expression. C/EBP?(+/-) mice exhibit an increase in bone density compared with C/EBP?(+/+) controls. These discoveries establish C/EBP? as the key transcriptional regulator of OC lineage commitment, providing a unique therapeutic target for diseases of excessive bone resorption, such as osteoporosis and arthritis.
| S-EPMC3645589 | biostudies-literature
Project description:Alternative splicing (AS) is involved in cell fate decisions and embryonic development. However, regulation of these processes is poorly understood. Here, we have identified the serine threonine kinase receptor-associated protein (STRAP) as a putative spliceosome-associated factor. Upon Strap deletion, there are numerous AS events observed in mouse embryoid bodies (EBs) undergoing a neuroectoderm-like state. Global mapping of STRAP-RNA binding in mouse embryos by enhanced-CLIP sequencing (eCLIP-seq) reveals that STRAP preferably targets transcripts for nervous system development and regulates AS through preferred binding positions, as demonstrated for two neuronal-specific genes, Nnat and Mark3. We have found that STRAP involves in the assembly of 17S U2 snRNP proteins. Moreover, in Xenopus, loss of Strap leads to impeded lineage differentiation in embryos, delayed neural tube closure, and altered exon skipping. Collectively, our findings reveal a previously unknown function of STRAP in mediating the splicing networks of lineage commitment, alteration of which may be involved in early embryonic lethality in mice.
| S-EPMC7684319 | biostudies-literature
Project description:The identity of cellular populations that drive liver regeneration after injury is the subject of intense study, and the contributions of polyploid hepatocytes to organ regeneration and homeostasis have not been systematically assessed. Here, we developed a multicolor reporter allele system to genetically label and trace polyploid cells in situ. Multicolored polyploid hepatocytes undergo ploidy reduction and subsequent re-polyploidization after transplantation, providing direct evidence of the hepatocyte ploidy conveyor model. Marker segregation revealed that ploidy reduction rarely involves chromosome missegregation in vivo. We also traced polyploid hepatocytes in several different liver injury models and found robust proliferation in all settings. Importantly, ploidy reduction was seen in all injury models studied. We therefore conclude that polyploid hepatocytes have extensive regenerative capacity in situ and routinely undergo reductive mitoses during regenerative responses.
| S-EPMC7204404 | biostudies-literature
Project description:Elucidation of the role of different cell lineages in the liver could offer avenues to drive liver regeneration. Previous studies showed that SOX9+ hepatocytes can differentiate into ductal cells after liver injuries. It is unclear whether SOX9+ hepatocytes are uni- or bipotent progenitors at a single-cell level during liver injury. Here, we developed a genetic tracing system to delineate the lineage potential of SOX9+ hepatocytes during liver homeostasis and regeneration. Fate-mapping data showed that these SOX9+ hepatocytes respond specifically to different liver injuries, with some contributing to a substantial number of ductal cells. Clonal analysis demonstrated that a single SOX9+ hepatocyte gives rise to both hepatocytes and ductal cells after liver injury. This study provides direct evidence that SOX9+ hepatocytes can serve as bipotent progenitors after liver injury, producing both hepatocytes and ductal cells for liver repair and regeneration.
| S-EPMC6409431 | biostudies-literature
Project description:Mutation of the retinoblastoma gene (RB1) tumour suppressor occurs in one-third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma. Numerous functions have been ascribed to the product of the human RB1 gene, the retinoblastoma protein (pRb). The best known is pRb's ability to promote cell-cycle exit through inhibition of the E2F transcription factors and the transcriptional repression of genes encoding cell-cycle regulators. In addition, pRb has been shown in vitro to regulate several transcription factors that are master differentiation inducers. Depending on the differentiation factor and cellular context, pRb can either suppress or promote their transcriptional activity. For example, pRb binds to Runx2 and potentiates its ability to promote osteogenic differentiation in vitro. In contrast, pRb acts with E2F to suppress peroxisome proliferator-activated receptor gamma subunit (PPAR-gamma), the master activator of adipogenesis. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that pRb might play a role in the choice between these two fates. However, so far, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis. Our data show that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.
| S-EPMC2933655 | biostudies-other
Project description:Molecular mechanisms underlying prostate and urothelial development remain unclear. This situation presents major limitations in identifying the cell type(s) and molecular events involved in the development of prostate and bladder cancer. It has been shown that mice lacking the basal cell marker p63 present several epithelial defects, including epidermis and prostate buds agenesis and urothelial abnormalities. Here, we use the p63-/- mouse as a tool to define cell lineages in the prostate epithelium and urothelium. By complementing p63-/- blastocysts with p63+/+ beta-galactosidase (beta-gal)-positive ES cells, we show that secretory cells of the prostate originate from p63-positive basal progenitor cells. Importantly, our urogenital sinus transplantation studies demonstrate that p63 prevents intestinal differentiation of the urogenital sinus endoderm and is therefore required to maintain commitment to the prostate cell lineage. Finally, in contrast with the prostate findings, analysis of the urothelium from rescued p63-/- chimeras shows that umbrella (superficial) cells can develop and be maintained independently from p63-positive basal and intermediate cells.
| S-EPMC1183537 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-01-28 | GSE122385 | GEO