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Effects of HIF2α in renal cancer metastasis and sensitivity to repurposed drugs

ABSTRACT: Effects of HIF2α in renal cancer metastasis and sensitivity to repurposed drugs

PROVIDER: PRJNA643786 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12135913_1.fastq.gz	Fastqsanger.gz
	SRR12135913_2.fastq.gz	Fastqsanger.gz
	SRR12135914_1.fastq.gz	Fastqsanger.gz
	SRR12135914_2.fastq.gz	Fastqsanger.gz
	SRR12135915_1.fastq.gz	Fastqsanger.gz

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Effects of HIF2α in renal cancer metastasis and sensitivity to repurposed drugs

Project description:Background: in clear cell renal cell carcinoma (ccRCC), 80% of cases have biallelic inactivation of VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods: we generated the 786-0 HIF2α knockout (KO) cell line and assessed the HIF2α antagonist PT2385 in several steps of tumour development. RNA sequencing was performed to identify genes differentially expressed between them and a drug screening was used to identify drugs with differential effects on HIF2α-expressing and KO cells. Results: HIF2α KO promoted cell migration, reduced proliferation and clonogenicity, as well as metastasis, whereas PT2385 treatment only inhibited tumour cell invasion. There was a large set of co-ordinately regulated genes, but HIF2α KO cells also had up-regulation of genes related to EMT and downregulation of genes involving cell migration and extracellular matrix. The HIF2α KO increased sensitivity to statins, while PT2385 had no effect. Conclusions: this study shows new pathways that could be targeted combined with PT2385 to enhance its therapeutic effects and delay resistance.

2021-08-11 | GSE153711 | GEO

Differential effects of HIF2α antagonist and HIF2α silencing in renal cancer and sensitivity to repurposed drugs.

Project description:BackgroundIn clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed.MethodsWe assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385.ResultsPT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity.Conclusionsthis study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

| S-EPMC8344147 | biostudies-literature

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs

Project description:Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs

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Reversal of Cancer Gene Expression Identifies Repurposed Drugs for Diffuse Intrinsic Pontine Glioma

Project description:Reversal of Cancer Gene Expression Identifies Repurposed Drugs for Diffuse Intrinsic Pontine Glioma

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Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling

Project description:Using a combination of single-cell RNAseq methods and murine pulmonary hypertension models, we show HIF2α overexpressing pericytes’ transformation into SMC-like cells, confirming HIF2α as a major molecular regulator in hypoxia-induced pulmonary hypertension (PH) and vascular remodeling. We demonstrate that HIF2α overexpression in pericyte-dominant transgenic mice exacerbates PH and right ventricular hypertrophy (RVH), whereas disruption of HIF2α expression attenuates the development of PH.

2024-08-25 | GSE211985 | GEO

Blood Biomarkers for Memory: Towards Early Detection of Risk for Alzheimer Disease, Pharmacogenomics, and Repurposed Drugs

Project description:Blood Biomarkers for Memory: Towards Early Detection of Risk for Alzheimer Disease, Pharmacogenomics, and Repurposed Drugs

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Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling [lung]

Project description:Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension(PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells(SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here we report that hypoxia-inducible factor 2α(HIF2α) expression is increased in human PAH patient lung tissues and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension(PH) models, we show HIF2α as a major molecular regulator for pericytes’ transformation into SMC-like cells. HIF2α overexpression in pericyte-selective mice exacerbate PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the potential role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.

2023-12-11 | GSE249461 | GEO

MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

Project description:MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

2019-11-19 | GSE123364 | GEO

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression [array]

Project description:Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNAdemethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

2017-08-23 | GSE102994 | GEO

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression [RNA-Seq]

Project description:Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

2017-06-28 | GSE100568 | GEO

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