Myc-dependent gene activation and repression in oncogene-addicted liver tumors
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PROVIDER: PRJNA306159 | ENA |
REPOSITORIES: ENA
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Project description:Tumors driven by activation of the transcription factor Myc generally show oncogene addiction. However, the gene-expression programs that depend upon sustained Myc activity in those tumors remain unknown. We have addressed this issue in a model of liver carcinoma driven by a reversible tet-Myc transgene, combining gene expression profiling with the mapping of Myc and RNA Polymerase II on chromatin. Switching off the oncogene in advanced carcinomas revealed that Myc is required for the continuous activation and repression of distinct sets of genes, constituting no more than half of those deregulated during tumor progression, and an even smaller subset of all Myc-bound genes. We further showed that a Myc mutant unable to associate with the co-repressor protein Miz1 is defective in the initiation of liver tumorigenesis. Altogether, our data provide the first detailed analysis of a Myc-dependent transcriptional program in a fully developed carcinoma, revealing that the critical effectors of Myc in tumor maintenance must be included within defined subsets (ca. 1,300 each) of activated and repressed genes.
2016-04-18 | GSE76062 | GEO
Project description:Tumors driven by activation of the transcription factor Myc generally show oncogene addiction. However, the gene-expression programs that depend upon sustained Myc activity in those tumors remain unknown. We have addressed this issue in a model of liver carcinoma driven by a reversible tet-Myc transgene, combining gene expression profiling with the mapping of Myc and RNA Polymerase II on chromatin. Switching off the oncogene in advanced carcinomas revealed that Myc is required for the continuous activation and repression of distinct sets of genes, constituting no more than half of those deregulated during tumor progression, and an even smaller subset of all Myc-bound genes. We further showed that a Myc mutant unable to associate with the co-repressor protein Miz1 is defective in the initiation of liver tumorigenesis. Altogether, our data provide the first detailed analysis of a Myc-dependent transcriptional program in a fully developed carcinoma, revealing that the critical effectors of Myc in tumor maintenance must be included within defined subsets (ca. 1,300 each) of activated and repressed genes.
2016-04-18 | GSE76042 | GEO
Project description:The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Em-tTA/tetO-MYC T-acute lymphomablastic lymphoma (T-ALL), some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express high levels of either transgenic or endogenous Myc suggesting that tumors continue to be addicted to oncogenic levels of MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator (tTA) resulting in expression of the MYC transgene even in the presence of doxycycline. Many of the remaining recurring tumors expressed high levels of endogenous Myc which was in some cases associated with a genomic rearrangement of the endogenous Myc locus or overexpression of Notch1. Gene expression profiling confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis confirming that these tumors remain oncogene addicted. These results suggest that tumors caused by MYC overexpression remain addicted to high levels of expression of this oncogene. 13 samples, no replicates included
2011-09-23 | E-GEOD-32341 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-04-18 | GSE76078 | GEO
Project description:Rhabdomyosarcomas are oncogene addicted to the activation of AVIL
| PRJNA749758 | ENA
Project description:The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Em-tTA/tetO-MYC T-acute lymphomablastic lymphoma (T-ALL), some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express high levels of either transgenic or endogenous Myc suggesting that tumors continue to be addicted to oncogenic levels of MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator (tTA) resulting in expression of the MYC transgene even in the presence of doxycycline. Many of the remaining recurring tumors expressed high levels of endogenous Myc which was in some cases associated with a genomic rearrangement of the endogenous Myc locus or overexpression of Notch1. Gene expression profiling confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis confirming that these tumors remain oncogene addicted. These results suggest that tumors caused by MYC overexpression remain addicted to high levels of expression of this oncogene.
2011-09-24 | GSE32341 | GEO
Project description:Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, MARS-AVIL formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS. We first showed that MARS-AVIL translates into an in-frame fusion protein, which is critical for the RMS cell tumorigenesis. Besides forming a gene fusion with the housekeeping gene, MARS, the AVIL locus is often amplified, and its RNA and protein expression is overexpressed in the majority of RMSs. Tumors with AVIL dysregulation exhibit evidence of oncogene addiction: silencing MARS-AVIL in cells harboring the fusion, or silencing AVIL in cells with AVIL overexpression, nearly eradicated the cells in culture, as well as inhibited in vivo xenograft growth in mice. Conversely, gain-of-function manipulations of AVIL led to increased cell growth and migration, enhanced foci formation in mouse fibroblasts, and most importantly transformed mesenchymal stem cells in vitro and in vivo. Mechanistically, AVIL seems to serve as a converging node functioning upstream of two oncogenic pathways, PAX3-FOXO1 and RAS, thus connecting two types of RMS associated with these pathways. Interestingly, AVIL is overexpressed in other sarcoma cells as well, and its expression correlates with clinical outcomes, with higher levels of AVIL expression being associated with worse prognosis. AVIL is a bona fide oncogene in RMS, and RMS cells are addicted to its activity.
2022-06-07 | GSE180837 | GEO
Project description:In mammalian cells, the Myc oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, Myc promotes an increase in expression of virtually all genes. In contrast, Myc-driven tumour cells differ from normal cells in expression of specific sets of up- and downregulated genes that have significant prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of Myc in human cells and murine tumour models. Changes in Myc levels activate and repress specific sets of direct target genes that are characteristic of Myc-transformed tumour cells. Three factors account for this specificity: First, the magnitude of response parallels the change in occupancy by Myc at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by Myc, arguing that different cellular responses to physiological and oncogenic Myc levels are controlled by promoter affinity. Secondly, Myc both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with Miz1 mediates repression of multiple target genes by Myc and the ratio of Myc and Miz1 bound to each promoter correlates with the direction of response. Myc, Miz1 and RNA polymerase II ChIPseq as well as RNAseq experiments in two human cancer cell lines and murine carcinoma cells as well as fibroblasts from Miz1M-bM-^HM-^FPOZ mice. All sequencing experiment were performed on an Illumina Genome Analyzer IIx.
2014-07-10 | E-GEOD-44672 | biostudies-arrayexpress
Project description: Not available
| S-EPMC6859582 | biostudies-literature
Project description:Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.
2005-07-21 | E-SMDB-2975 | biostudies-arrayexpress