Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA280722 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1958950_1.fastq.gz | Fastqsanger.gz | |||
| SRR1958950_2.fastq.gz | Fastqsanger.gz | |||
| SRR1958960_1.fastq.gz | Fastqsanger.gz | |||
| SRR1958960_2.fastq.gz | Fastqsanger.gz | |||
| SRR1958970_1.fastq.gz | Fastqsanger.gz |
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Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC). To explore ITH in detail, multiple tumor samples were taken from the primary renal tumors of mRCC patients who were sunitinib treated (n=23) or untreated (n=23). ITH of pathological grade, DNA (using array-based comparative genomic hybridisation), RNA (Illumina Beadarray) and protein (reverse phase protein array) were evaluated. Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). Unsupervised and supervised analysis, for renal cancer driver, hypoxia and stromal gene signatures, was then performed. In untreated patient tumor samples, significant ITH occurred in chromosomal aberrations, RNA and protein expression, with clustering of DNA and RNA correlating for individual patients. In unsupervised analysis sunitinib therapy was not associated with increased ITH in DNA or RNA. However there was an increase in ITH for the driver mutation and hypoxia gene signatures (DNA and RNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and RNA changes to targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples. Together these findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes. The results do not support the hypothesis that resistant clones are selected and predominate after initiation of targeted therapy; instead it appears that an initial clonal diversification occurs, supporting the hypothesis of polyclonal drug resistance. 128 samples from patients with clear cell renal cell carcinoma, including biological replicates of nephrectomy samples. Source of samples includes both biopsy and nephrectomy. DNA extracted from FFPE and fresh frozen tissue samples.
2015-05-25 | E-GEOD-67818 | biostudies-arrayexpress
Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC). To explore ITH in detail, multiple tumor samples were taken from the primary renal tumors of mRCC patients who were sunitinib treated (n=23) or untreated (n=23). ITH of pathological grade, DNA (using array-based comparative genomic hybridisation), RNA (Illumina Beadarray) and protein (reverse phase protein array) were evaluated. Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). Unsupervised and supervised analysis, for renal cancer driver, hypoxia and stromal gene signatures, was then performed. In untreated patient tumor samples, significant ITH occurred in chromosomal aberrations, RNA and protein expression, with clustering of DNA and RNA correlating for individual patients. In unsupervised analysis sunitinib therapy was not associated with increased ITH in DNA or RNA. However there was an increase in ITH for the driver mutation and hypoxia gene signatures (DNA and RNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and RNA changes to targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples. Together these findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes. The results do not support the hypothesis that resistant clones are selected and predominate after initiation of targeted therapy; instead it appears that an initial clonal diversification occurs, supporting the hypothesis of polyclonal drug resistance.
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Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC). 138 samples from patients with clear cell renal cell carcinoma, including biological replicates of nephrectomy samples. RNA extracted fresh frozen tissue samples.
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Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC).
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Project description:<p>Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a novel mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies</p>
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Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression data from metastatic 786-M1A cells with and without reintroduced HA-VHL. The empty vector, pBabe-puro, was used as control.
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Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression data from 786-O cells after 3-day treatment with 100uM 5’-aza-deoxycytidine (5DC) or vehicle (DMSO).
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Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.
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Project description:Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies.
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