Bulk RNAseq of murine gliomas driven by overexpression of PDGFB
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA783316 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17029635.fastq.gz | Fastqsanger.gz | |||
| SRR17029636.fastq.gz | Fastqsanger.gz | |||
| SRR17029637.fastq.gz | Fastqsanger.gz | |||
| SRR17029639.fastq.gz | Fastqsanger.gz | |||
| SRR17029642.fastq.gz | Fastqsanger.gz |
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Project description:Here we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies.
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Project description:Glioblastoma progression remains elusive, especially in its first stages. Here, by simultaneous transfer of PDGFB and genetic barcode in mouse brain, we triggered gliomagenesis in univocally labelled cells in vivo, hence enabling direct tracing of glioblastoma evolution from the earliest possible stage. We observed an unexpectedly high incidence of clonal extinction events and progressive clonal size divergence, even after the acquisition of a malignant phenotype. Computational modelling suggests these dynamics as the consequence of a clonal-based cell-cell competition. Bulk and single-cell transcriptome analyses, coupled to lineage tracing, revealed that the strongest correlation with clonal size unbalancing is shown by Myc transcriptional targets. Additionally, higher levels of Myc signalling discriminate "winner" from "loser" clones in early gliomagenesis. These results agree with recent understanding of the Myc-mediated induction of supercompetitive phenotype in mammalian embryo. Our findings shed light on aspects of glioblastoma evolution inaccessible by conventional retrospective approaches and highlight the potential of the combined use of clonal tracing and transcriptomic analyses in this field.
2023-07-18 | GSE189577 | GEO
Project description:We performed genome-wide profiling of oligodendrocyte lineage transcription factor 2 (Olig2) and other histone markers in platelet-derived growth factor subunit B (PDGFB)-induced glioma and genome-occupancy analyses coupled with transcriptome profiling to reveal gene regulatory network. Examination of Olig2, H327Ac, and H3K4me3 genome-wide occupancy in PDGFB-induced Ctrl-T and Olig2cKO brain tumors (gliomas).
2016-05-17 | E-GEOD-80088 | biostudies-arrayexpress
Project description:Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting.We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identify functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.
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Project description:BackgroundMalignant gliomas, the most common malignant brain tumors in adults, represent a heterogeneous group of diseases with poor prognosis. Retroviruses can cause permanent genetic alterations that modify genes close to the viral integration site.MethodsHere we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next-generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies.ResultsA large fraction of common integration sites contained genes that have been dysregulated or misexpressed in glioma. Others overlapped with loci identified in previous glioma-related forward genetic screens, but several novel putative cancer-causing genes were also found. Integrating retroviral tagging and clinical data, Ppfibp1 was highlighted as a frequently tagged novel glioma-causing gene. Retroviral integrations into the locus resulted in Ppfibp1 upregulation, and Ppfibp1-tagged cells generated tumors with shorter latency on orthotopic transplantation. In human gliomas, increased PPFIBP1 expression was significantly linked to poor prognosis and PDGF treatment resistance.ConclusionsAltogether, the current study has demonstrated a novel approach to tagging glioma genes via forward genetics, validating previous results, and identifying PPFIBP1 as a putative oncogene in gliomagenesis.
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Project description:Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal childhood brain tumors. Their unique genetic makeup, pathological heterogeneity, and brainstem location all present challenges to treatment. Developing mouse models that accurately reflect each of these distinct features will be critical to advance our understanding of DIPG development, progression, and therapeutic resistance. The aim of this study was to generate new mouse models of DIPG, and characterize the role of specific oncogenic combinations in DIPG pathogenesis. We used in utero electroporation (IUE) to transfect neural stem cells in the developing brainstem with PiggyBac DNA transposon plasmids. Combinations of PDGFB or PdgfraD842V, dominant negative Trp53 (DNp53), and H3.3K27M expression induced fully penetrant brainstem gliomas. IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 induced the rapid development of grade-IV gliomas. PdgfraD842V + DNp53 produced slower forming grade-III gliomas. Addition of H3.3K27M only significantly accelerated PdgfraD842V DIPG development. Glioma subgroup molecular signatures were associated with differences in bulk PDGFB and PdgfraD842V tumor composition. H3.3K27M induced both overlapping and unique gene expression changes in PDGFB and PdgfraD842V tumors. Paracrine effects of PDGFB promote disruption of pericyte-endothelial interactions and angiogenesis in PDGFB DIPG mouse models. Brainstem targeted in utero electroporation provides a rapid and flexible system to generate diverse DIPG mouse models. Using IUE to investigate mutation and pathohistological heterogeneity of DIPG will provide a valuable tool for future genetic and preclinical studies.
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Project description:Non-canonical roles for growth factors in the nucleus have been previously described, but their mechanism of action and biological roles remain enigmatic. Platelet-derived growth factor B (PDGFB) can drive formation of low-grade glioma and here we show that it localizes to the nucleus of human glioma cells where it binds chromatin to preserve genome stability and cell lineage. Failure of PDGFB to localize to the nucleus leads to chromosomal abnormalities, aberrant heterochromatin architecture and accelerated tumorigenesis. Furthermore, nuclear localization of PDGFB is reliant upon the expression levels and mutation status of isocitrate dehydrogenase (IDH). Unexpectedly, we identified macrophages as the predominant source of PDGFB in human, finding that immune-derived PDGFB can localize to the nucleus of glioma cells. Collectively, these studies show that immune derived PDGFB enters the nucleus of glioma cells to maintain genomic stability, while identifying a new mechanism by which IDH mutations promote gliomagenesis.
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