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Conserved patterns of transcriptional dysregulation, heterogeneity and cell states in clear cell kidney cancer [Bulk RNA-seq]

ABSTRACT: Clear cell kidney cancers (ccRCC) stem from proximal tubule cells in which the VHL gene has been disrupted, causing activation of HIF transcription factors. Although this is essential for cancer initiation, it not sufficient for development of aggressive tumors. To better understand transcriptional programs underpinning ccRCC progression, we perform single cell transcriptomics on 75 kidney tumor and patient-matched normal kidney biopsies. We describe tumor dysregulated transcriptional programs that are conserved across patients, deconvoluted by cell type. Leveraging recurrent intratumor heterogeneity in chromosome 14q loss, a metastasis-associated copy number alteration, we describe the ensuing transcriptional programs to reveal potential mechanisms priming cells for metastasis. Lastly, we describe co-existing cancer cell states consistently found in all patients, underpinned by distinct transcriptional regulators and whose transcriptional signatures are prognostic. These cancer cell states reflect heterogeneity found in the normal proximal tubule epithelium, strongly indicating that they arise from lineage plasticity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269819 | GEO | 2024/12/18

REPOSITORIES: GEO

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Conserved patterns of transcriptional dysregulation, heterogeneity and cell states in clear cell kidney cancer [scRNA-seq]

Project description:Clear cell kidney cancers (ccRCC) stem from proximal tubule cells in which the VHL gene has been disrupted, causing activation of HIF transcription factors. Although this is essential for cancer initiation, it not sufficient for development of aggressive tumors. To better understand transcriptional programs underpinning ccRCC progression, we perform single cell transcriptomics on 75 kidney tumor and patient-matched normal kidney biopsies. We describe tumor dysregulated transcriptional programs that are conserved across patients, deconvoluted by cell type. Leveraging recurrent intratumor heterogeneity in chromosome 14q loss, a metastasis-associated copy number alteration, we describe the ensuing transcriptional programs to reveal potential mechanisms priming cells for metastasis. Lastly, we describe co-existing cancer cell states consistently found in all patients, underpinned by distinct transcriptional regulators and whose transcriptional signatures are prognostic. These cancer cell states reflect heterogeneity found in the normal proximal tubule epithelium, strongly indicating that they arise from lineage plasticity.

2024-12-18 | GSE269826 | GEO

Cell profiling of acute kidney injury reveals conserved cellular responses to injury

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Project description:Clear cell renal cell carcinomas (ccRCC) are characterized by arm-wide chromosomal alterations. Loss at 14q is associated with disease aggressiveness in ccRCC, which responds poorly to chemotherapeutics. The 14q locus contains one of the largest miRNA clusters in the human genome; however, little is known about the contribution of these miRNAs to ccRCC pathogenesis. In this regard, we investigated the expression pattern of selected miRNAs at the 14q32 locus in TCGA kidney tumors and in ccRCC cell lines. We validated that the miRNA cluster is downregulated in ccRCC (and cell lines) as well as in papillary kidney tumors relative to normal kidney tissues and primary renal proximal tubule epithelial (RPTEC) cells. We demonstrated that agents modulating expression of DNMT1 (e.g., 5-Aza-deoxycytidine) could modulate miRNA expression in ccRCC cell lines. Lysophosphatidic acid (LPA, a Lysophospholipid mediator elevated in ccRCC) not only increased labile iron content but also modulated expression of 14q32 miRNAs. Through an overexpression approach targeting a subset of 14q32 miRNAs (specifically at subcluster A: miR-431, miR-432, miR-127, and miR-433) in 769-P cells, we uncovered changes in cellular viability and claudin-1, a tight junction marker. A global proteomic approach was implemented using these miRNA overexpressing cell lines which uncovered ATXN2 as a highly downregulated target, which has a role in chronic kidney disease pathogenesis. Collectively, these findings support a contribution of miRNAs at 14q32 in ccRCC pathogenesis.

2023-05-10 | PXD036428 | Pride

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Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (up-to 70% of all RCC types). There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL and nearly 100% familial ccRCC (in VHL disease) contain VHL deficiency. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation and this solid tumor contains a substantial number of infiltrated immune cells. This indicates that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory microenvironment. In this study we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to ccRCC formation, and found that human macrophages induced by VHL-deficient kidney tubule cells exhibit distinct gene expression program containing the signatures of tumor-associated macrophages that can promote ccRCC progression.

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Early Signaling Events in Renal Compensatory Hypertrophy Revealed by Multi-Omics

Project description:Loss of a kidney results in compensatory growth of the remaining kidney, a phenomenon of considerable clinical importance. However, the mechanisms involved are largely unknown. Here, we used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. Morphometry applied to microdissected proximal tubules showed that growth of the proximal tubule involves a marked, rapid increase in cell volume rather than cell number. Measurements of DNA accessibility (ATAC-seq), transcriptome (RNA-seq) and proteome (quantitative protein mass spectrometry) independently identified patterns of change that are indicative of activation of the lipid-regulated transcription factor, PPARα. Activation of PPARα by fenofibrate administration increased proximal tubule cell size, while genetic deletion of PPARα in mice decreased it. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.

2023-06-05 | PXD036395 | Pride

Effect of GW4064 on primary cultured mouse kidney proximal tubule cells

Project description:Global gene expression in the primary cultured mouse kidney proximal tubule cells treated either DMSO or 1uM GW4064 (a FXR agonist) was compared. Results provide insight into mechanisms underlying effects of FXR activation on gene expression in mouse kidney proximal tubule cells. Male C57/BJ mice aged 6 weeks were sacrificed under anesthesia and kidney proximal tubule cells were cultured until confluent. Cells were treated with either GW4064 (1uM) or equal amount of DMSO and incubated for 24 hours. 4 total RNA samples per group were analyzed and gene expression was compared between the groups.

2015-06-26 | E-GEOD-70296 | biostudies-arrayexpress

Transcriptomes of Major Proximal-Tubule Cell-Culture Models

Project description:Purpose:Cultured cell lines are widely used for research in the physiology, pathophysiology, toxicology and pharmacology of the renal proximal tubule. The lines that are most appropriate for a given use depend on the genes expressed.We have used modern RNA-sequencing techniques to identify the gene expression profile of 14 different cell lines plus primary cultures of mouse proximal tubule and compare them to transcriptomes of native kidney proximal tubules. Methods: 14 different proximal tubule cell lines were grown on permeable supports under conditions specific for the respective lines. RNA-Seq followed standard procedures. Results and conclusion: Transcripts expressed in cell lines showed variable match to transcripts selectively expressed in native proximal tubule. Opossum kidney (OK) cells displayed the highest percentage match (45%) with pig kidney cells (LLC-PK1) close behind (39%). Much lower percentage matches were seen for various human lines including HK-2 cells (26%) and lines from rodent kidneys (18-23%).An online resource (https://esbl.nhlbi.nih.gov/JBrowse/KCT/) has been created for interrogation of the data.No cell line closely matched the transcriptome of native proximal tubule cells. However, some of the lines tested are suitable for the study of particular metabolic and transport processes seen in the proximal tubule.

2020-10-14 | GSE135441 | GEO

Effect of GW4064 on primary cultured mouse kidney proximal tubule cells

Project description:Global gene expression in primary cultured mouse kidney proximal tubule cells treated with either DMSO or 1uM GW4064 (an FXR agonist) was compared. Results provide insight into mechanisms underlying effects of FXR activation on gene expression in mouse kidney proximal tubule cells.

2015-06-26 | GSE70296 | GEO

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