Single-Cell RNA Sequencing in Multiple Pathologic Types of Renal Cell Carcinoma Revealed Novel Potential Tumor-Specific Markers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE152938 | GEO | 2021/10/04
REPOSITORIES: GEO
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Project description:In order to address the progression, metastasis, and clinical heterogeneity of renal cell cancer (RCC), transcriptional profiling with oligonucleotide microarrays (22,283 genes) was done on 49 RCC tumors, 20 non-RCC renal tumors, and 23 normal kidney samples. Samples were clustered based on gene expression profiles and specific gene sets for each renal tumor type were identified. Gene expression was correlated to disease progression and a metastasis gene signature was derived. Gene signatures were identified for each tumor type with 100% accuracy. Differentially expressed genes during early tumor formation and tumor progression to metastatic RCC were found. Subsets of these genes code for secreted proteins and membrane receptors and are both potential therapeutic or diagnostic targets. A gene pattern ("metastatic signature") derived from primary tumors was very accurate in classifying tumors with and without metastases at the time of surgery. A previously described "global" metastatic signature derived by another group from various non-RCC tumors was validated in RCC. Unlike previous studies, we describe highly accurate and externally validated gene signatures for RCC subtypes and other renal tumors. Interestingly, the gene expression of primary tumors provides us information about the metastatic status in the respective patients and has the potential, if prospectively validated, to enrich the armamentarium of diagnostic tests in RCC. We validated in RCC, for the first time, a previously described metastatic signature and further showed the feasibility of applying a gene signature across different microarray platforms. Transcriptional profiling allows a better appreciation of the molecular and clinical heterogeneity in RCC. We used the following tissue samples to obtain transcriptional profiling of kidney tumors using Affymetrix HGU-133A chips: 23 Normal, 32 clear cell RCC (cRCC), 11 papillary RCC (pRCC), 6 chromophobe RCC (chrRCC), 12 Oncocytoma (OC), and 8 transitional cell carcinoma (TCC). The supplementary file 'GSE15641_mas5_data.txt' contains MAS5 signal values for the Samples included in Series GSE15641. This dataset is part of the TransQST collection.
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Project description:Clear cell renal cell carcinoma (ccRCC) is the most common variant of kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Here, we report that the RING ligase praja2 is a novel component of the endocytic system that supports clathrin-mediated receptor endocytosis. At the molecular level, we identify the adaptor protein AP2 as a binding partner and substrate of praja2. Functionally, we demonstrate that praja2 is required for AP2-mediated receptor endocytosis and clearance. Downregulation of praja2 in RCC cells and tissues is associated with a marked upregulation of membrane receptors, as EGFR, VEGFR and TfR. A negative feedback loop links EGF signaling to proteolysis of praja2 and sustains downstream mitogenic and proliferative pathways. Restoring praja2 expression in RCC cells remarkably decreases EGFR levels, rewires cancer cell metabolism and inhibits RCC growth and metastatic diffusion. In praja2 knockout mice, upregulation of RTKs levels associates with profound histopathological renal alterations. Our findings identify praja2 as a component of the endocytic pathway that supports receptor endocytosis and clearance. Downregulation of praja2 in RCC cells, thus, sustains RTK signaling and promotes kidney cancer growth and diffusion.
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Project description:Each total RNA sample is hybridized to two different arrays: Affymetrix U133A (GPL96) and U133B (GPL97). For most of the normal tissue samples there is a renal clear cell carcinoma sample from the same patient. There is no matching tumor sample for normal sample N1. For most of the renal clear cell carcinoma samples there is a corresponding adjacent normal tissue sample from the same patient. There are no matching normal tissue samples for C011 or C032. Keywords = kidney Keywords = renal Keywords = RCC Keywords = carcinoma Keywords = cancer Keywords: parallel sample
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Project description:Each total RNA sample is hybridized to two different arrays: Affymetrix U133A (GPL96) and U133B (GPL97). For most of the normal tissue samples there is a renal clear cell carcinoma sample from the same patient. There is no matching tumor sample for normal sample N1. For most of the renal clear cell carcinoma samples there is a corresponding adjacent normal tissue sample from the same patient. There are no matching normal tissue samples for C011 or C032. Keywords = kidney Keywords = renal Keywords = RCC Keywords = carcinoma Keywords = cancer Keywords: parallel sample
2003-11-25 | GSE781 | GEO
Project description:In recent years, several approaches have been taken in the peptide-based immunotherapy of metastatic renal cell carcinoma (RCC), although little is known about HLA presentation on metastases compared to primary tumor and normal tissue of RCC. In this study we compared primary tumor, normal tissue and metastases with the aim of identifying similarities and differences between these tissues. We performed this comparison for two RCC patients on the level of the HLA ligandome using mass spectrometry and for three patients on the level of the transcriptome using oligonucleotide microarrays. The quantitative results show that primary tumor is more similar to metastasis than to normal tissue, both on the level of HLA ligand presentation and mRNA. We were able to characterize a total of 142 peptides in the qualitative analysis of HLA-presented peptides. Six of them were significantly overpresented on metastasis, among them a peptide derived from CD151; fourteen were overpresented on both primary tumor and metastasis compared to normal tissue, among them an HLA ligand derived from tumor protein p53. Thus, we could demonstrate that peptide-based immunotherapy might affect tumor as well as metastasis of RCC, but not healthy kidney tissue. Furthermore we were able to identify several peptides derived from tumor-associated antigens that are suitable for vaccination of metastatic RCC. Three clear cell renal cell carcinomas including autologous normal tissue and autologous metastasis were analyzed. This dataset is part of the TransQST collection.
2008-09-03 | E-GEOD-12606 | biostudies-arrayexpress
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common variant of kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Here, we report that the RING ligase praja2 is a novel component of the endocytic system that supports clathrin-mediated receptor endocytosis. At molecular level, we identify the adaptor protein AP2 as a binding partner and substrate of praja2. Functionally, we demonstrate that praja2 is required for AP2-mediated receptor endocytosis and clearance. Downregulation of praja2 in RCC cells and tissues is associated with a marked upregulation of membrane receptors, as EGFR, VEGFR and TfR. A negative feedback loop links EGF signaling to proteolysis of praja2 and sustains downstream mitogenic and proliferative pathways. Restoring praja2 expression in RCC cells remarkably decreases EGFR levels, rewires cancer cell metabolism and inhibits RCC growth and metastatic diffusion. In praja2 knockout mice, upregulation of RTKs levels associates with profound histopathological renal alterations. Our findings identify praja2 as a component of the endocytic pathway that supports receptor endocytosis and clearance. Downregulation of praja2 in RCC cells, thus, sustains RTK signaling and promotes kidney cancer growth and diffusion.
2023-08-13 | E-MTAB-11900 | biostudies-arrayexpress
Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and elucidating the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Method: Expression studies of RING ligase praja2 and tyrosine kinase receptors (RTKs) in renal cell carcinoma was evaluated by immunoblot and immunohistochemistry. Gene transcription profiling in RCC cells was evaluated by RNA sequencing and Ingenuity Pathway Analysis. Imunofluorescence assays were used to evaluate the intracellular distribution and clearance of membrane receptors in cells devoid of praja2. Ubiquitin modifications and protein-protein interaction networks were monitored by IP, western blot, mass spectrometry and proteomic analysis. Experiments in vitro and in vivo were performed to define the role of praja2 in RTKs turnover, metabolism, renal cell carcinoma growth and metastatic diffusion. Results: We report here that the ubiquitin ligase praja2 controls endocytosis and the signal strength of different types of receptors (EGFR, VEGFR, TfR). Praja2 forms a complex with- and ubiquitinates the adaptor protein AP2m required for the activity of ATPase and acidification of endosomes and lysosomes necessary for receptor endocytosis and clearance. Downregulation of praja2 blocks the endocytosis of several membrane receptors, including EGFR, VEGFR and TfR and amplifies mitogenic and proliferative signaling as shown in the clear cell renal cell carcinoma (ccRCC). Restoring praja2 expression in RCC cells reduces EGFR levels, rewires cancer cell metabolism and inhibits growth and metastatic diffusion. In vivo, praja2 knockout mice show upregulation of tyrosine kinase receptors (RTKs) and pronounced histopathological renal alterations. Conclusion: Our findings identify praja2 as an important regulator of tyrosine kinase receptor(s) turnover and can be considered a bona fide oncosuppressor because it finely regulates signaling of several types of receptors and its loss supports kidney cancer growth and diffusion.
2024-02-01 | E-MTAB-13105 | biostudies-arrayexpress