Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA260644 | ENA |
REPOSITORIES: ENA
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Project description:How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared to their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the events taking place between initial mutation and a fully developed tumor mass (pre-malignant phase) are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs, and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the pre-malignant phase, which revealed a dynamic multi-step transformation, starting with rapid but transient hyper-proliferative reactivation, followed by a long period of dormancy, then final malignant transformation. Using pharmacological approaches, we discovered that mTOR signaling is critical for both the initial OPC reactivation step and late stage tumor cell proliferation, and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs, and reveal an actionable multi-phasic reactivation process that turns slowly dividing OPCs into malignant gliomas. 44K Mouse Development Oligo Microarrays from Agilent Technologies were used for microarray analysis. For each experiment, total RNA was fluorescently labeled and hybridized directly against a common reference sample generated from the RNA pool of four WT P17 mouse brain neocortex.
2014-09-09 | E-GEOD-61282 | biostudies-arrayexpress
Project description:How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared to their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the events taking place between initial mutation and a fully developed tumor mass (pre-malignant phase) are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs, and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the pre-malignant phase, which revealed a dynamic multi-step transformation, starting with rapid but transient hyper-proliferative reactivation, followed by a long period of dormancy, then final malignant transformation. Using pharmacological approaches, we discovered that mTOR signaling is critical for both the initial OPC reactivation step and late stage tumor cell proliferation, and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs, and reveal an actionable multi-phasic reactivation process that turns slowly dividing OPCs into malignant gliomas.
2014-09-09 | GSE61282 | GEO
Project description:Genomic and transccriptomic landscape of two step malignant transformation process.
| PRJEB37468 | ENA
Project description:To identify a novel miRNA that is aberrantly expressed in GICs, we analyzed differences in miRNA expression between the mouse GICs, NSCL61 and OPCL61, showing characteristic features of cancer stem cell, and their parental cells by miRNA microarrays. neural stem cells, glioma-initiating cells (GICs) from neural stem cells, oligodendrocyte precursor cells, glioma-initiating cells (GICs) from oligodendrocyte precursor cells.
2015-04-07 | E-GEOD-61080 | biostudies-arrayexpress
Project description:Background: Glioma is a kind of highly heterogeneous central nervous system malignancy and controlled by various molecular processes such as neoplastic transformation, dysregulation of the cell cycle, and angiogenesis. Among these biomolecular events, the existence of inflammation and stress pathways in the development and driving factors of glioma heterogeneity has been reported. However, mechanisms of glioma heterogeneous under stress response remain unclear, especially from a spatial aspect. Methods: This study combined single-cell and spatially resolved transcriptomics and revealed that oxidative stress response genes play a vital role in oligodendrocyte precursor cells from two different types of gliomas: high- and low-grade (HG and LG). Results: In HG, stress triggers metabolic pattern changes from oxidative phosphorylation to glycolysis to avoid apoptosis, along with epithelial-to-mesenchymal transition and increased expression of genes of stress response. Scenic analysis indicated that oxidative stress induced the activation of AP1 in HG, thus enhancing the tumor survival and proliferation process. Conclusion: When all of these factors are considered together, we provide a unique perspective on how oxidative stress response occurs in different grades of gliomas, which would deepen our understanding of evolution and heterogeneity in gliomas.
2024-06-23 | GSE270355 | GEO
Project description:Cancer results from molecular mutations occurring in specific cell types, thus determining the cell-of-origin is critical for effective cancer treatment. Inferring such information from terminal tumors can be misleading because malignant tumor cells tend to acquire aberrant properties. Animal models are widely used because one can initiate mutations in specific cell types. However, cell-of-mutation that harbors initial molecular changes may not directly transform, rather merely passes along mutations to its progeny cell lineage, which then serves as cell-of-origin and finally transforms into malignancy. Such a problem is exemplified in the glioma field: glioma can be induced either by mutating tumor suppressor genes in neural stem cells (NSCs) or by over-expressing oncogenes in restricted progenitor cells such as oligodendrocyte precursor cells (OPCs). However, for the NSC glioma model, it remains unknown whether NSCs directly transform or simply pass along mutations to OPC lineage for malignancy. Here we use a genetic system termed Mosaic Analysis with Double Markers (MADM) to study the earliest stage of gliomagenesis from mutated NSCs. At an in vivo single-cell resolution, we unbiasedly analyzed tumorigenic potential of NSCs and all cell lineages derived from them. At pathologically undetectable pre-transforming phases, we found no significant aberrant growth of mutant NSCs and their derivatives except for the OPC lineage. We then tracked the tumor progression from earliest stage and confirmed the expansion of OPCs lead to gliomagenesis. Consistently, transcriptome profiling reveals that terminal-stage tumor cells display salient OPC features and resemble human proneural subtype of glioblastoma multiform (GBM). Most importantly, introducing the same mutations directly into OPCs was sufficient for malignant transformation and these tumor cells are indistinguishable in their gene expression profiles from those in which the first mutations were introduced into NSCs. Our findings strongly implicate OPCs as the transforming cell type for glioma even when initial mutations could occur in NSCs, and highlight the importance of analyzing early phases of tumorigenesis to distinguish cell-of-origin from cell-of-mutation. 44K Mouse Development Oligo Microarrays from Agilent Technologies were used for microarray analysis. For each experiment, total RNA was fluorescently labeled and hybridized directly against a common reference sample generated from the RNA pool of four WT P17 mouse brain neocortex.
2011-07-01 | E-GEOD-26676 | biostudies-arrayexpress
Project description:Cancer stem cells play key roles in human malignancies. However, their cellular and molecular origins are still poorly understood. Here we report the successful generation of cancer stem cells from primary human astrocytes by use of defined genetic factors. Combined transduction of four factors âmyc, Oct-4, p53DD, and rasâ induced efficient transformation of primary human astrocytes into malignant cells with powerful tumor-initiating capabilities. Transplantation of 100 of the cells into nude mice is sufficient for tumor formation. The cells also showed unlimited self-renewal ability with robust telomerase activities. In addition, they expressed typical glioma stem cell markers such as CD133, CD15, and CD90. Moreover, transformed cells could form spheres in culture and differentiate into neuron-astrocyte-, and oligodendrocyte-like cells. They also displayed significant resistance to temozolomide. These induced cancer stem cells (iCSCs) should be useful for both tumor biology studies and therapeutics development. This record contains data from microarray analysis of normal human astrocytes, two transduced cell lines (OCT4+3G and OCT4+6G), a patient-derived glioma stem cell line (ALPS1459) and a glioblastoma cell line (U87MG).
2016-11-07 | E-MTAB-4771 | biostudies-arrayexpress
Project description:Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients’ survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of stem cell-like malignant cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural precursor cell-like, astrocyte cell-like, and oligodendrocyte precursor-like, alongside oligodendrocytes and neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associated with decreased survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients’ plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.
2024-03-20 | GSE240704 | GEO
Project description:The osteogenic differentiation process consists in a well-coordinated multi-step sequence of events, in which each stage is characterized by the expression of distinct protein markers, as well as by individual morphological features. In order to precisely identify the step at which cells are permissive to MET-driven transformation, we used expression profiling. We compared the transcriptional profiles of MET-HOB and MSC cells where osteoblast differentiation was induced.
2013-02-28 | GSE28205 | GEO
Project description:Oncogenic transformation of lung epithelial cells is a multi-step process, frequently starting with the inactivation of tumor suppressors and subsequent activating mutations in proto-oncogenes, such as members of the PI3K or MAPK family. Cells undergoing transformation have to adjust to changes, such as metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors, which manifest these adjustments. Here, we report that the deubiquitylase USP28 enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes, such as c-JUN, c-MYC, NOTCH and ∆NP63, at early stages of malignant transformation. USP28 is increased in cancer compared to normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors, such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small molecule inhibitor reset the proteome of transformed cells towards a ‘pre-malignant’ state, and its inhibition cooperated with clinically established compounds used to target EGFRL858R, BRAFV600E or PI3KH1047R driven tumor cells. Targeting USP28 protein abundance already at an early stage via inhibition of its activity therefore is a feasible strategy for the treatment of early stage lung tumours and the observed synergism with current standard of care inhibitors holds the potential for improved targeting of established tumors.
2022-04-08 | PXD032810 | Pride