Mutation of the cell cycle regulator p27Kip1 drives pseudohypoxic pheochromocytoma development
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ABSTRACT:
PROVIDER: PRJNA684044 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13237413_1.fastq.gz | Fastqsanger.gz | |||
| SRR13237413_2.fastq.gz | Fastqsanger.gz | |||
| SRR13237414_1.fastq.gz | Fastqsanger.gz | |||
| SRR13237414_2.fastq.gz | Fastqsanger.gz | |||
| SRR13237415_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Pseudohypoxic tumors activate pro-oncogenic pathways typically associated with severe hypoxia even when sufficient oxygen is present, leading to highly aggressive tumors. Prime examples are pseudohypoxic pheochromocytomas and paragangliomas (p-PPGLs), neuroendendocrine tumors currently orphan of effective therapy. Previous attempts to generate mouse models for p-PPGLs all failed. Here, we describe that the rat MENX line, carrying a Cdkn1b (p27) frameshift-mutation, spontaneously develops pseudohypoxic pheochromocytoma (p-PCC). Methods: We compared rat p-PCCs with their cognate human tumors at different levels: histology, immunohistochemistry, catecholamine profiling, electron microscopy, transcriptome and metabolome. Vessels architecture and angiogenic potential of PCCs was analyzed by light-sheet fluorescence microscopy ex vivo and multi-spectral optoacoustic tomography (MSOT) in vivo. Results: Analysis of tissues at various stages, from hyperplasia to advanced grades, allowed us to correlate tumor characteristics with progression. Pathological changes affecting mitochrondrial ultrastructure where present already in hyperplasias. Rat PCCs secreted high levels of norepinephrine and dopamine. Transcriptomic and metabolomic analysis revealed changes in oxidative phosphorylation that aggravated over time, leading to an accumulation of the oncometabolite 2-hydroxyglutarate, and to hypermethylation, evident by loss of the epigenetic mark 5-hmC. While rat PCC xenografts showed high oxygenation, induced by massive neoangiogenesis, rat PCC transcriptomes possessed a pseudohypoxic signature of high Hif2a, Vegfa, and low Pnmt expression, thereby clustering with human p-PPGL. Conclusion: Endogenous rat PCCs recapitulate key phenotypic features of human p-PPGLs. Thus, MENX rats emerge as the best available animal model of these aggressive tumors. Our study provides evidence of a link between cell cycle dysregulation and pseudohypoxia.
2021-01-13 | GSE162970 | GEO
Project description:Pseudohypoxic tumors activate pro-oncogenic pathways typically associated with severe hypoxia even when sufficient oxygen is present, leading to highly aggressive tumors. Prime examples are pseudohypoxic pheochromocytomas and paragangliomas (p-PPGLs), neuroendendocrine tumors currently lacking effective therapy. Previous attempts to generate mouse models for p-PPGLs all failed. Here, we describe that the rat MENX line, carrying a Cdkn1b (p27) frameshift-mutation, spontaneously develops pseudohypoxic pheochromocytoma (p-PCC). We compared rat p-PCCs with their cognate human tumors at different levels: histology, immunohistochemistry, catecholamine profiling, electron microscopy, transcriptome and metabolome. The vessel architecture and angiogenic potential of pheochromocytomas (PCCs) was analyzed by light-sheet fluorescence microscopy ex vivo and multi-spectral optoacoustic tomography (MSOT) in vivo. The analysis of tissues at various stages, from hyperplasia to advanced grades, allowed us to correlate tumor characteristics with progression. Pathological changes affecting the mitochrondrial ultrastructure where present already in hyperplasias. Rat PCCs secreted high levels of norepinephrine and dopamine. Transcriptomic and metabolomic analysis revealed changes in oxidative phosphorylation that aggravated over time, leading to an accumulation of the oncometabolite 2-hydroxyglutarate, and to hypermethylation, evident by the loss of the epigenetic mark 5-hmC. While rat PCC xenografts showed high oxygenation, induced by massive neoangiogenesis, rat primary PCC transcriptomes possessed a pseudohypoxic signature of high Hif2a, Vegfa, and low Pnmt expression, thereby clustering with human p-PPGL. Endogenous rat PCCs recapitulate key phenotypic features of human p-PPGLs. Thus, MENX rats emerge as the best available animal model of these aggressive tumors. Our study provides evidence of a link between cell cycle dysregulation and pseudohypoxia.
| S-EPMC7794757 | biostudies-literature
Project description:MENX is a rat multiple endocrine neoplasia syndrome caused by a homozygous mutation of the Cdkn1b gene, encoding p27Kip1. Affected rats develop adrenomedullary hyperplasia which progresses to pheochromocytoma with time (incidence 100%), and to extra-adrenal pheochromocytoma (paraganglioma) (68%). We here report that hyperplasia and tumor have similar gene expression profiles, suggesting an early determination of the tumorigenic signature. Overexpressed genes in rat adrenal lesions are especially enriched in development/differentiation-associated genes.
2010-11-19 | GSE21006 | GEO
Project description:Until now, it is nearly impossible to diagnose malignancy of pheochromocytoma/paraganglioma with pathological examinations. The aim of the study is to find the genes which can be applied as a biomarker in the clinic to distinguish benign and malignant forms of pheochromocytoma/paraganglioma.
2014-08-17 | GSE60457 | GEO
Project description:Low levels of the cell cycle regulator p27Kip1 are associated with a worse outcome in many tumor types. We report here a new regulatory role of p27Kip1 as a transcriptional regulator. In association with transcriptional repressors such as p130, E2F4 and HDACs, p27 binds to promoters of multiple genes leading to their repression. The p27Kip1-target genes participate in RNA processing, translation, respiration and cell cycle. Remarkably, p27Kip1-target genes are over-expressed in different human tumors in tight association with a poor clinical prognosis. We also observed a clear correlation between low levels of p27Kip1 and over-expression of p27Kip1-target genes in tumors. Overall, our findings indicate new tumor suppressor roles of p27Kip1 as a transcriptional regulator of genes relevant for oncogenesis.
2011-12-01 | GSE20064 | GEO
Project description:Low levels of the cell cycle regulator p27Kip1 are associated with a worse outcome in many tumor types. We report here a new regulatory role of p27Kip1 as a transcriptional regulator. In association with transcriptional repressors such as p130, E2F4 and HDACs, p27 binds to promoters of multiple genes leading to their repression. The p27Kip1-target genes participate in RNA processing, translation, respiration and cell cycle. Remarkably, p27Kip1-target genes are over-expressed in different human tumors in tight association with a poor clinical prognosis. We also observed a clear correlation between low levels of p27Kip1 and over-expression of p27Kip1-target genes in tumors. Overall, our findings indicate new tumor suppressor roles of p27Kip1 as a transcriptional regulator of genes relevant for oncogenesis. Samples from MEFs p27delta51 and p27WT cells used as control were analyzed
2011-12-01 | E-GEOD-20064 | biostudies-arrayexpress
Project description:Pheochromocytoma has attracted much attention as a kind of neuroendocrine tumor with the highest genetic correlation in all types of tumors. Detailedly, the frequency of germline mutation in pheochromocytoma is as high as about 40%, and the mutation frequency of von Hippel Lindau (VHL) is the highest in all pheochromocytoma genes. However, the effects of VHL mutation on proteome of pheochromocytoma have remained unexplored. In this study, we compared and analyzed the proteomics of VHL-deficient and VHL WT PC12 cell line. It is showed that expressional level of 434 proteins (fold change > 1.3, VHL shRNA/WT) was significantly changed by VHL deficiency. Furthermore, the functions of these proteins were predicted by gene ontology (GO) and Kyoto Protocol Encyclopedia of Genes and Genomes (KEGG). Of the 434 proteins, 83 proteins, involved in cell proliferation, cell cycle, cell migration, and so on, were interpreted their complex regulatory relationships using String database. More importantly, we discovered 7 novel critical genes whose expression were up-regulated due to VHL deficiency, including Connective Tissue Growth Factor (CTGF), Syndecan Binding Protein (SDCBP), Cysteine Rich Protein 61 (CYR61/CCN1), Collagen Type III Alpha 1 Chain (COL3A1), Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type V Alpha 2 Chain (COL5A2) and Serpin Family E Member 1 (SERPINE1), which may be related to cell proliferation and migration in VHL-mutated pheochromocytoma tumor samples. These results indicate that deficiency of VHL would promote the development of pheochromocytoma by activating expression of genes associated with cell proliferation and migration.
2021-03-11 | PXD021190 | Pride
Project description:Cytogenetic analysis of 36 pheochromocytoma and four paraganglioma using high density arrays
2014-09-21 | GSE61594 | GEO
Project description:Transcriptional analysis of 84 primary pheochromocytoma (PCC)/paraganglioma tumors.
2010-12-31 | GSE19422 | GEO
Project description:Genome wide DNA methylation profiling of pheochromocytoma/paraganglioma samples carrying different mutations. The Illumina Infinium EPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles.
2018-12-11 | GSE111336 | GEO