Gene expression profiling of aneuploid IMR90 cells induced by Rb, DNMT1 and MAD2 depletion
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PROVIDER: PRJNA493820 | ENA |
REPOSITORIES: ENA
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Project description:Segregation errors of chromosomes into daughter cells lead to aneuploidy that is considered a major feature of solid tumors. How diploid cells face chromosome mal-segregation and the mechanisms driving aneuploidy tolerance in tumor cells are not yet completely defined. Thus, an important goal in cancer genetics is to identify gene networks leading to aneuploidy as well involved in its tolerance. To this aim we induced aneuploidy in IMR90 human primary cells and analyzed their gene expression profiles by DNA microarrays. Bioinformatics analysis revealed the presence of shared differentially expressed genes, up or down regulated in IMR90 cells after depletion of pRb, DNMT1 and MAD2 all inducing aneuploidy. Normalized data were also analyzed with the Gene Set Enrichment Analysis (GSEA) software to detect deregulated gene-sets associated with the aneuploidy phenotype. GSEA analysis suggested the existence of shared gene-sets/pathways characterizing aneuploidy cells that might be exploited for novel therapeutic approaches in cancer
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Project description:Mad2 and p53 loss were combined in liver or T-cells specificely leading to early onset and highly aggressive aneuploid HCC and T-ALL. Tumours were characterized for (recurrrent) copy number changes with a focus on whole chromosome abnormalities. DNA content was compared to the DNA content of sex-matched uninfiltrated control liver samples from litter mates Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.
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Project description:Inhibition of an initiating oncogene often leads to extensive tumor cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anti-cancer agents. Whether chromosomal instability (CIN) generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumors, has any effect on oncogene addiction, however, has not been explored systematically. We show here that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 does not affect the regression of Kras driven lung tumors upon Kras inhibition. However, tumors that experience transient Mad2 overexpression and consequent chromosome instability recur at dramatically elevated rates. The recurrent tumors are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early CIN may be responsible for tumor relapse after seemingly effective anti-cancer treatments.
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Project description:Inhibition of an initiating oncogene often leads to extensive tumor cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anti-cancer agents. Whether chromosomal instability (CIN) generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumors, has any effect on oncogene addiction, however, has not been explored systematically. We show here that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 does not affect the regression of Kras driven lung tumors upon Kras inhibition. However, tumors that experience transient Mad2 overexpression and consequent chromosome instability recur at dramatically elevated rates. The recurrent tumors are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early CIN may be responsible for tumor relapse after seemingly effective anti-cancer treatments. Experiment Overall Design: Lung tumor tissue from TI-K (CCSP-rtTA;TRE-KrasV12), TI-KM (CCSP-rtTA; TRE-KrasV12; TRE-Mad2), recurrence (TI-KM) or normal lung tissue (CCSP-rtTA) was subjected to RNA extraction and individual samples hybridized to array platform MOE430A 2.0 Affymetrix.
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Project description:The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many of chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability, and hence controls the DNA methylation status in the promoter of at least Ink4a, Shc2, FoxO6 and Noggin genes. Further, we demonstrate that inactivation of pRB promotes the Tip60 (acetyltransferase)-dependent ATM activation, allows activated ATM to physically bind to DNMT1 forming a complex with Tip60 and UHRF1 (E3 ligase), and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of pRB pathway in coordination with aberration in DNA damage response leads to abnormal DNA methylation pattern by affecting the stability of DNMT1.
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