EGFR/FOXO3a/BIM signalling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide
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ABSTRACT:
PROVIDER: PRJNA589752 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10461717_1.fastq.gz | Fastqsanger.gz | |||
| SRR10461717_2.fastq.gz | Fastqsanger.gz | |||
| SRR10461718_1.fastq.gz | Fastqsanger.gz | |||
| SRR10461718_2.fastq.gz | Fastqsanger.gz | |||
| SRR10461719_1.fastq.gz | Fastqsanger.gz |
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Project description:Accumulating evidence suggests that glioma stem cells (GSCs), rare cells characterised by pluripotency and self-renewal, are responsible for glioblastoma (GBM) propagation, recurrence and resistance to therapy. Differentiation with bone morphogenic proteins (BMPs) is considered to be a promising approach to eliminate GSCs and sensitise glioma to chemotherapeutics. Epidermal growth factor receptor (EGFR) gene alterations are detected in more than a half of GBMs, however, the role of EGFR in chemoresistance of glioma stem cells remain elusive. Here, we investigated whether EGFR signalling affects BMP4-induced differentiation of GSCs and their response to an alkylating drug temozolomide (TMZ). We show that BMP4 triggers Smad signalling cascade in glioma stem cells independently of the EGFR level. BMP4 down-regulated levels of pluripotency markers (SOX2 and OLIG2) with the concomitant induction of astrocytic (GFAP) and neuronal (b-Tubulin III) markers. However, significant differences in chemotherapy outcomes were observed in glioma stem cells with different EGFR levels. BMP4-induced differentiation did not enhance sensitivity to TMZ in EGFRlow GSCs, in contrast to EGFRhigh GSCs, which were undergoing apoptosis. We identified differences in cell cycle regulation by analyses of cell cycle phase distribution and cell-cycle-related proteins. In cells with lower EGFR expression BMP4 triggered the G1 cell cycle arrest, not detected in EGFRhigh cells. RNA-seq profiles further highlighted transcriptomic alternations and distinct processes characterizing EGFR-dependent responses in course of BMP4-induced differentiation. We identified AKT/FOXO3a axis controlling of BIM (the pro-apoptotic BCL-2 family protein) as operating only in EGFRhigh BMP4-differentiated and TMZ-treated cells.
2021-05-05 | GSE140441 | GEO
Project description:Accumulating evidence suggests that glioma stem cells (GSCs), which are rare cells characterized by pluripotency and self-renewal ability, are responsible for glioblastoma (GBM) propagation, recurrence and resistance to therapies. Bone morphogenic proteins (BMPs) induce GSC differentiation, which leads to elimination of GSCs and sensitization of glioma to chemotherapeutics. Alterations in the epidermal growth factor receptor (EGFR) gene are detected in more than half of GBMs; however, the role of EGFR in the chemoresistance of GSCs remains unknown. Here, we examined whether EGFR signaling affects BMP4-induced differentiation of GSCs and their response to the alkylating drug temozolomide (TMZ). We show that BMP4 triggers the SMAD signaling cascade in GSCs independent of the EGFR level. BMP4 downregulated the levels of pluripotency markers (SOX2 and OLIG2) with a concomitant induction of an astrocytic marker (GFAP) and a neuronal marker (β-Tubulin III). However, GSCs with different EGFR levels responded differently to treatments. BMP4-induced differentiation did not enhance sensitivity to TMZ in EGFRlow GSCs, in contrast to EGFRhigh GSCs, which underwent apoptosis. We then identified differences in cell cycle regulation. In EGFRlow cells, BMP4-triggered G1 cell cycle arrest which was not detected in EGFRhigh cells. RNA-seq profiles further highlighted transcriptomic alterations and distinct processes characterizing EGFR-dependent responses in the course of BMP4-induced differentiation. We found that the control of BIM (the pro-apoptotic BCL-2 family protein) by the AKT/FOXO3a axis only operated in BMP4-differentiated EGFRhigh cells upon TMZ treatment.
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Project description:The molecular events that are involved in the establishment and the maintenance of CD4+ Central Memory (TCM) and Effector Memory (TEM) T cells are poorly understood. Using global gene expression profiling, single cell proteomics, and functional assays, we show that the survival of TCM CD4+ T cells involves the activation and phosphorylation of STAT5a and FOXO3a. STAT5a phosphorylation induces the transcriptional up-regulation of anti-apoptotic genes specifically in TCM. The phosphorylation of FOXO3a at S315, following TCR engagement, prevents the transcription of pro-apoptotic gene like FasL and BIM. Experiments aimed at blocking FOXO3a phosphorylation confirmed the role of FOXO3a in protecting TCM from apoptosis. Our results define the underlying molecular mechanisms responsible for the longevity and persistence of CD4+ TCM. Keywords: comparative gene profile, cell-type comparison, central memory to Effector memory
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Project description:The poor prognosis of patients with glioblastoma is partly due to resistance to standard treatment, which combines chemoradiation using temozolomide (TMZ). The concept of cancer stem cells provided new insight into tumor resistance and management, and isolated Glioblastoma stem-like cells (GSCs) which contribute to this therapy resistance. Bone morphogenetic protein 4 (BMP4) is a differentiation factor that stimulates astroglial differentiation of such GSCs, thereby reducing their self-renewal. Exposing GSCs to BMP4 could therefore sensitize them to chemotherapy with TMZ, but previous studies with various treatment paradigms have produced contradictory results in this matter. Therefore, we re-defined the optimal treatment paradigm for the combination of TMZ and BMP4 and subsequently re-assessed the inter-tumoral variability in response to co-treatment with TMZ+BMP4 in vitro. First, the simultaneous treatment was found more effective than sequential therapy. Second, after application of our optimized treatment protocol, 70% of a total of 20 patient-derived glioblastoma cultures showed synergy when the treatments were combined. The synergistic effect was a result of increased cellular apoptosis and not of decreased proliferation. Comparative RNA-sequencing suggested that combination treatment results in decreased MAPK signaling. We conclude that addition of BMP4 to standard therapy with TMZ could enlarge the group of patients with good therapeutic response.
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Project description:To explore the underlying molecular mechanisms of FOXO3A-regulated AML cell function To determine the impact of FOXO3A deficiency on AML cells, we generated knock-out (KO) cells of FOXO3A using small guide RNAs (sgRNAs)
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2013-01-12 | E-GEOD-43452 | biostudies-arrayexpress
Project description:Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and often associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators, we have analyzed the protein secretome of human endothelial cells in the presence of sEng. We find that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased levels of BMP4 transcripts in lungs and increased circulating BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appears 18 days after mating, precisely coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 are positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the pathobiology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.
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Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma.
2013-05-01 | GSE42762 | GEO
Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
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