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P53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (ChIP-Seq)

ABSTRACT: The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identified tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces a canonical senescence response in a subset of tumors, while, in others, p53 induces a non-apoptotic form of cell death that culminates in necrosis. We pinpointed the cyclophilin family of peptidyl prolyl cis-trans isomerases as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines that are poised to undergo p53- mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that a previously unappreciated intertumoral heterogeneity in SCLC can influence the biological response to p53 restoration, describes a novel mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.

ORGANISM(S): Mus musculus

PROVIDER: GSE231701 | GEO | 2023/06/05

REPOSITORIES: GEO

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p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq II)

Project description:The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identified tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces a canonical senescence response in a subset of tumors, while, in others, p53 induces a non-apoptotic form of cell death that culminates in necrosis. We pinpointed the cyclophilin family of peptidyl prolyl cis-trans isomerases as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines that are poised to undergo p53- mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that a previously unappreciated intertumoral heterogeneity in SCLC can influence the biological response to p53 restoration, describes a novel mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.

2023-06-05 | GSE231704 | GEO

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq I)

2023-06-05 | GSE231703 | GEO

Mouse small cell lung cancer model

Project description:A mouse model for human small cell lung carcinoma (SCLC) has been developed based on evidence in human tumors that the tumor suppressor functions of RB and p53 are defective in more than 90% of SCLC cases. We also developed another mouse model also combines loss of p130 (Rbl2), an RB-related gene, with deletion of RB and p53. These two mouse tumors were shown to closely resemble human SCLC. The goal of this array experiment is to assess genome-wide gene expression of those mouse tumors and determine the similarity of the mouse models to human SCLC. Gene expression from Mouse Rb/p53 ( n=10 ) and Rb/p53/p130 primary tumors ( n=3 ) as well as tumor-free adult mouse lungs ( n=2 ) was measured using the Affymetrix GeneChip Mouse Genome 430-2.0 arrays.

2010-06-08 | E-GEOD-18534 | biostudies-arrayexpress

Mouse small cell lung cancer model

2010-06-01 | GSE18534 | GEO

Cyclophilin B supports the survuval of glioblastoma multiforme cells

Project description:We have found that cyclophilin B (CypB) expression is important for malignant glioblastoma multiforme (GBM) cell proliferation. To identify molecular mechanisms that could explain CypB-dependent survival in human GBM cells, a microarray analysis was performed using RNA prepared from U251MG GBM cells transduced with lentiviral CypB shRNA. These data revealed that about 130 genes were more than 2-fold affected by CypB depletion. Significant alterations in the expression of genes related to cell death, cell proliferation and cell migration were found in the shCypB cells. U251 glioblastoma cells transduced with lentivirus expressing non-target control shRNA (shCON) were compared to cells transduced with lentivirus expressing shRNA sequence against cyclophilin B (shCypB). Cells transduced with the lentiviral shRNA (shCON VS shCypB) for 5 days before total RNA extraction. Three biological replicates of cells treated with each shRNA (shCON or shCypB) were profiled.

2013-09-12 | E-GEOD-50756 | biostudies-arrayexpress

Cyclophilin A isomerization of Septin 2 mediates abscission during cytokinesis

Project description:The isomerase activity of Cyclophilin A is important for midbody abscission during cell division, however to date, midbody substrates remain unknown. In this study, we report that the GTP-binding protein Septin 2 interacts with Cyclophilin A. We highlight a dynamic series of Septin 2 phenotypes at the midbody, previously undescribed in human cells. Furthermore, Cyclophilin A depletion or loss of isomerase activity is sufficient to induce phenotypic Septin 2 defects at the midbody. Structural and molecular analysis reveals that Septin 2 proline 259 is important for interaction with Cyclophilin A. Moreover, an isomerisation-deficient EGFP-Septin 2 proline 259 mutant displays defective midbody localisation, and undergoes impaired abscission, consistent with data from cells with loss of Cyclophilin A expression or activity. Collectively, this data reveals Septin 2 as a novel interacting partner and isomerase substrate of Cyclophilin A at the midbody that is required for abscission during cytokinesis in cancer cells.

2023-10-24 | PXD042822 | Pride

IDH1R132H activity in glioma cell lines and tumnor tissue (2HG)

Project description:We developed genetically engineered mice to generate brain tumors with especific genetic lessions. The animals were split in three groups: NRAS, P53 knockdown, IDH1-R132H and ATRX knock down (NPAID); NRAS, P53 knockdown, IDH1-R132H (NPI); NRAS, P53 knockdown, (NshP53). From these tumor we obtain and culture tumor cells growth like neurospheres and attached cells.

2015-03-05 | ST000312 | MetabolomicsWorkbench

Array CGH-based Characterization of Genetic Alterations in Pulmonary Neuroendocrine Tumors

Project description:The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on Array Comparative Genomic Hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal (GI) carcinoids. In contrast to the relatively stable karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. Recurrent CN alterations of a total of 203 genes, including the RB1 gene, and 59 microRNAs, most of which locate in the DLK1-DIO3 domain, were observed in SCLC tumors, bronchial carcinoids and carcinoids of GI origin; in contrast, CN alterations of the TP53 gene and the MYC family members were observed more frequently in SCLC. These findings suggest the existence of partially shared tumor-specific CN alterations in these tumors. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resemble that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC. Carcinoids, including 19 bronchial carcinoids and 9 carcinoid of gastrointestinal origin, and small cell lung cancer, including 33 patients' tumor samples and 13 cell line samples, were compared.

2010-04-22 | E-GEOD-21468 | biostudies-arrayexpress

Cyclophilin D-dependent mitochondrial permeability transition amplifies inflammatory reprogramming in endotoxemia

Project description:We aimed to understand the role of cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of lipopolysaccharide (LPS)-induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, on liver RNA sequencing (RNAseq) data, Ingenuity® Pathway Analysis (IPA ®) was used to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2715 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll-like receptors (TLRs), and tumor necrosis factor α receptors (TNFRs) mediated processes in wild-type mice. The disruption of CypD reduced the LPS-induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO- and ROS-producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear- and mitochondrial-encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD-dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases.

2019-03-07 | GSE79059 | GEO

Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition [thyroid]

Project description:This study assessed tumor suppressor roles of CREBBP in SCLC and other neuroendocrine tumors. Genetically engineered mouse models were used to determine the tumor suppressor role of Crebbp in SCLC and other neuroendocrine tumors.

2018-10-17 | GSE117551 | GEO

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