Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE148196 | GEO | 2022/06/06
REPOSITORIES: GEO
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Project description:BackgroundGlioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4.MethodsCell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures.ResultsHigh variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4.ConclusionThe changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.
| S-EPMC9713526 | biostudies-literature
Project description:Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers
| PRJNA623424 | ENA
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.
| EGAS00001007095 | EGA
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: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.
2020-04-23 | PXD016228 | Pride
Project description:In order to observe palovarotene modulates BMP4-induced transcriptome,2H11 cells treated with BMP4 or BMP4 plus palovarotene for 48 hours were subjected to RNAseq analyses
2021-03-04 | GSE168157 | GEO
Project description:Bone morphogenetic protein-4 (BMP4) is involved in regulation of neural stem cells (NSCs) proliferation, differentiation, migration and survival. It was previously thought that the treatment of NSCs with BMP4 alone induces astrocytes, whereas the treatment of NSCs with the bFGF/BMP4 combination induces quiescent neural stem cells (qNSCs). In this study, we performed RNA sequencing (RNA-Seq) to compare the transcriptome profiles of BMP4-treated NSCs and bFGF/BMP4-treated NSCs, and found that both NSCs treated by these two methods were Sox2 positive qNSCs which were able to generate neurospheres. However, NSCs treated by those two methods exhibited different characteristics in state and the potential for neuronal differentiation based on transcriptome analysis and experimental results. We found that BMP4-treated NSCs tended to be in a deeper quiescent state than bFGF/BMP4-treated NSCs as the percentage of ki67-positive cells were lower in BMP4-treated NSCs. And after exposure to differentiated environment, bFGF/BMP4-treated NSCs generated more DCX-positive immature neurons and MAP2-positive neurons than BMP4-treated NSCs. Our study characterized qNSCs treated with BMP4 alone and bFGF/BMP4 combination, which laid a foundation for studying the activation mechanism of qNSCs.
2024-06-26 | GSE267115 | GEO
Project description:MIXL1-GFP reporter lines were differentiated as Spin EBs in APEL medium supplemented with Wnt3a alone, BMP4 alone or Wnt3a/BMP4 in combination. EBs induced in the absence of growth factors were used as control. EBs induced with BMP4 or Wnt3a/BMP4 were FACS sorted based on E-CADHERIN and GFP expression. Unsorted EBs and sorted fractions were subjected to Illumina microarray processing.
2010-01-06 | E-MEXP-2495 | biostudies-arrayexpress
Project description:Growth suppressing Wnt/BMP4-Msx/Notch signalling in neuroblastoma
| PRJEB36530 | ENA
Project description:Compare transcriptomes of BMP4 and BMP4 plus Palo treatment in 2H11 cells
| PRJNA706370 | ENA