RNAseq of wild-type and VHL-deficient CD8+ subsets
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA657568 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12462577_1.fastq.gz | Fastqsanger.gz | |||
| SRR12462577_2.fastq.gz | Fastqsanger.gz | |||
| SRR12462578_1.fastq.gz | Fastqsanger.gz | |||
| SRR12462578_2.fastq.gz | Fastqsanger.gz | |||
| SRR12462579_1.fastq.gz | Fastqsanger.gz |
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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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Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).
2016-07-01 | E-GEOD-60422 | biostudies-arrayexpress
Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis.
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Project description:VHL loss is the most common genetic alteration event in ccRCC. We profiled histone modifications from VHL-deficient ccRCC primary tumors and cell lines. We show that ccRCCs exhibit a pervasive gain of enhancers around hypoxic and metabolic transcriptional targets. Motif analysis using HOMER revealed significant enrichment of AP-1, ETS, NFĸB and HIFα in tumor enhancers. We generated ChIP-seq binding data for c-Jun, ETS1, NFĸB, and P300, a histone acetyltransferase, in 786-O cells. ChIP-seq profiles of HIF2α and HIF1β in 786-O were already generated previously (GSE34871)
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Project description:Human Naïve-like CD8 T cells induced by the Yellow Fever Vaccine 17D were compared to the conventional subsets in total CD8 T cells Samples originate from peripheral blood mononuclear cells (PBMC) from 8 different donors vaccinated with the YF-17D vaccine 1'000 cells from various CD8 T cells subsets were purified by flow cytometry, from 8 vaccinees (donors d1 to d8); the subsets (cell types) include: A2/NS4b tetramer positive CCR7+ CD45RA+ CD8 T cells (A2_NS4b Naïve-like), Total Naive (CCR7+ CD45RA+), Total Tscm (CCR7+ CD45RA+ CD58+ CD95+), Total CM (CCR7+ CD45RA-) and Total Effectors (CCR7 negative).
2015-04-08 | E-GEOD-65804 | biostudies-arrayexpress
Project description:VHL loss is the most common genetic alteration event in ccRCC. By profiling histone modifications from VHL-deficient ccRCC primary tumors and cell lines, we identifed tumor-associated promoters and enhancers. We next investigate whether VHL restoration alters tumor associated promoters and enhancers. We compared H3K27ac ChIP-seq with and without VHL restoration in 786-O cells. Restoration of wild-type VHL significantly altered a subset of tumor enhancers but affected promoters to a less extent.
2017-08-22 | GSE102095 | GEO
Project description:The aim was to assess miRNA expression in 3 human ex-vivo CD8+ T cell subsets which span from antigen inexperienced cells (NaM-CM-/ve) to early memory cells (central memory, Tcm) and later stage memory cells (effector memory, Tem) CD8+ T cells were sorted on a FACS Aria II machine. N = naM-CM-/ve = CD8+, CCR7+, CD45RA+, CD45RO-, Tcm = central memory = CD8+, CCR7+, CD45RA-, CD45RO-,Tem= effector memory = CD8+, CCR7-, CD45RA-, CD45RO+ PBMC were isolated from 3 healthy human donors and sorted by FACS into 3 CD8+ T cell subsets. Total RNA was purified using the miRVANA kit (Ambion)
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Project description:Inactivation of the E3 ubiquitin ligase protein von Hippel-Lindau (VHL) is critical to clear cell renal cell carcinomas (ccRCC) and VHL syndrome. VHL loss leads to stabilization of hypoxia-inducible factor α (HIFα) and other substrate proteins, which may drive various tumor-promoting pathways. This process is likely reversible, because even in the highly aggressive human VHL-deficient ccRCC cell line 786-O, restoring VHL expression almost completely abolishes orthotopic tumor formation in immuno-deficient mice. This result highlights the potential of treating ccRCC by re-expressing VHL with gene therapy. However, there is inadequate understanding of the consequence of VHL restoration at the molecular level. Here, we reinstalled VHL expression in 786-O and performed transcriptome, proteome and ubiquitome profiling to assess the molecular impact.
2021-10-18 | GSE186013 | GEO