Effect of RRM2 knockdown on gene expression of NF1-associated MPNST cells
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ABSTRACT:
PROVIDER: PRJNA883419 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21678677_1.fastq.gz | Fastqsanger.gz | |||
| SRR21678677_2.fastq.gz | Fastqsanger.gz | |||
| SRR21678678_1.fastq.gz | Fastqsanger.gz | |||
| SRR21678678_2.fastq.gz | Fastqsanger.gz | |||
| SRR21678679_1.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the role of RRM2 in the progression of NF1-associated MPNST, we established S462TY cell in which target gene has been knocked down by shRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of control and knockdown of target gene group
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Project description:NF1-associated malignant peripheral nerve sheath tumors (MPNST) are the major cause of mortality in neurofibromatosis. MPNST arise from benign peripheral nerve plexiform neurofibromas (PN) which originate in the embryonic neural crest cell lineage. Using reporter transgenes that label early neural crest lineage cells in multiple NF1 MPNST mouse models, we discovered and characterized a rare MPNST cell population with stem cell-like properties that is essential for tumor initiation and relapse. Following isolation of these cells we derive a cancer stem cell specific gene expression signature that includes consensus embryonic neural crest genes and we also identify Nestin as a novel marker for the MPNST cell of origin. Finally, application of the mouse cancer stem cell signature to single cell sequencing data from a rare NF1-associated MPNST precursors called atypical neurofibromatosis neoplasms of uncertain biologic potential (ANNUBP), identifies preformed unsupervised gene expression cell clusters. Enrichment of the cancer stem cell signature in cognate human tumors supports the generality and relevance of cancer stem cells to therapy development.
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Project description:To investigate the function of p53 in regulating response to MET inhibition in MPNST cells we established NF1-MET;sgP53 cells in which Trp53 was knocked out using CRISPR-Cas9. As a control, the parental NF1-MET was transduced with CRISPR-Cas9 in the absence of sgRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of the 2 different cells treated with either capmatinib or vehicle in duplicate.
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Project description:We utilized three murine MPNST cell lines. 67C-4 and #5NPCIS cell lines are derived from spontaneously arising tumors in mice mutated for NF1 and p53 (so-called NP-cis mice; PMID: 12154062). SN4-4 cells originated from MPNST tumors induced by injecting adenovirus containing Cas9 and guide RNA for Nf1 and p53 into the sciatic nerves, resulting in NF1/p53-null MPNST (PMID: 32456131). We implanted 5 x 10^6 murine MPNST cells, subcutaneously, into the flanks of 6-8 weeks old gender-matched C57BL/6 mice (for 67C-4 and #5NPCIS) and BALB/c mice (for SN4-4 mice) to generate MPNST tumors. All mice were procured from Envigo. Upon reaching a size of 300-500 mm3, the mice were euthanized to harvest the tumors, which were subsequently flash frozen using liquid nitrogen and processed for RNA sequencing.
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Project description:Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST‐specific biomarkers for screening patients with NF1. Genome‐wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1‐MPNST cell lines was performed to identify and validate candidate MPNST‐specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST‐specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD‐seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature‐selection criteria and predictive modeling, we identified 73 candidate MPNST‐specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2‐fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be further investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1.
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Project description:Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST-specific biomarkers for screening patients with NF1. Genome-wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1-MPNST cell lines was performed to identify and validate candidate MPNST-specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST-specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD-seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature-selection criteria and predictive modeling, we identified 73 candidate MPNST-specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2-fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be further investigated as biomarkers in clinical settings for early MPNST detection in patients with NF1.
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within pre-existing benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation and respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST tumor models indicates that MEK inhibition has poor anti-tumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors was performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with hydroxychloroquine as a novel treatment approach for NF1 MPNSTs.
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Project description:Comparison of copy number changes in MPNST samples against benign neurofibromas in NF1 patients 24 MPNSTs and 3 NF samples were hybridised to the human 32K BAC tiling path array
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Project description:Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression
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Project description:Comparison of copy number changes in MPNST samples against benign neurofibromas in NF1 patients
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