Homo sapiens
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PROVIDER: PRJNA399710 | ENA |
REPOSITORIES: ENA
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Project description:Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression
| PRJNA399713 | ENA
Project description:Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression [RNA-Seq]
| PRJNA392124 | ENA
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
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
Project description:Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by HIF2α antagonists. We show that increasing BMAL1 sensitizes ccRCC-derived A498 cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.
2025-03-17 | GSE290669 | GEO
Project description:Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by HIF2α antagonists. We show that increasing BMAL1 sensitizes ccRCC-derived 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.
2025-03-17 | GSE269334 | GEO
Project description:BAP1 links epigenetic regulation of ferroptosis to tumor suppression
| PRJNA396084 | ENA
Project description:We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct (N1D), which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone. 6 neuroblastoma tumors were transfected with Notch1 decoy, 6 with Notch1 decoy and treated with bevacizumab, 6 tumors treated with bevacizumab, and 6 control tumors were profiled by human 133A 2.0 arrays
2013-12-01 | E-GEOD-48880 | biostudies-arrayexpress
Project description:High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential with tumors refractory to retinoic acid differentiation based therapies. Here, we leverage high-throughput drug screening of epigenetic targeted therapies across a large and diverse tumor cell line panel to uncover the hypersensitivity of neuroblastoma cells to GSK-J4, a small molecule dual inhibitor of H3K27 demethylases UTX and JMJD3. Mechanistically, GSK-J4 induced neuroblastoma differentiation and ER stress with accompanying upregulation of PUMA and apoptosis induction. Retinoic acid (RA)-resistant neuroblastoma cells were sensitive to GSK-J4. Additionally, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Further, GSK-J4 and RA combined to induce differentiation, ER-stress and limit the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, which is the most prevalent driver gene alteration in the refractory population, PUMA induction by GSK-J4 sensitized tumors to the BCL-2 inhibitor venetoclax, demonstrating that epigenetic targeted therapies and BH3 mimetics can be rationally combined to treat high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust anti-neuroblastoma activity.
2018-02-17 | GSE110709 | GEO
Project description:In this study, mRNA expression profiles of 113 primary untreated human neuroblastoma samples were compared with the aim to identify prognostic exon and gene sets as well as parameters associated with alternative exon use. The primary neuroblastoma specimens were from tumor banks in Cologne or Essen, Germany, Ghent, Belgium and Valencia, Spain. All patients were diagnosed between 1998 and 2007 and treated according to the German Neuroblastoma trials NB97, NB 2004 or the SIOPEN protocol. This submission contains 87 exon array profiles and are used together with exon array data from 26 Samples in GSE21713 (see 'Relation' links below) to predict the outcome of patients with neuroblastoma. The resulting dataset, which is linked below as a supplementary file ('GSE32664_complete_RMA_data.txt'), was used for the subsequent analyses.
2012-06-17 | E-GEOD-32664 | biostudies-arrayexpress