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Cdkn2a loss in a model of neurofibroma demonstrates stepwise tumor progression to atypical neurofibroma and MPNST

ABSTRACT: Cdkn2a loss in a model of neurofibroma demonstrates stepwise tumor progression to atypical neurofibroma and MPNST

PROVIDER: PRJNA623591 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11504663.fastq.gz	Fastqsanger.gz
	SRR11504664.fastq.gz	Fastqsanger.gz
	SRR11504665.fastq.gz	Fastqsanger.gz
	SRR11504666.fastq.gz	Fastqsanger.gz
	SRR11504667.fastq.gz	Fastqsanger.gz

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Cdkn2a loss in a model of neurofibroma demonstrates stepwise tumor progression to atypical neurofibroma and MPNST

Project description:Plexiform neurofibromas (PN) are benign nerve sheath Schwann cell tumors, common in patients with neurofibromatosis type 1 (NF1), that are characterized by biallelic mutations in the NF1 tumor suppressor gene. Atypical neurofibromas (ANF) show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). We combined loss of Nf1 in developing

2020-12-23 | GSE148249 | GEO

<i>Cdkn2a</i> Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST.

Project description:Plexiform neurofibromas are benign nerve sheath Schwann cell tumors characterized by biallelic mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene. Atypical neurofibromas show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). Here we combined loss of Nf1 in developing Schwann cells with global Ink4a/Arf loss and identified paraspinal plexiform neurofibromas and atypical neurofibromas. Upon transplantation, atypical neurofibromas generated genetically engineered mice (GEM)-PNST similar to human MPNST, and tumors showed reduced p16INK4a protein and reduced senescence markers, confirming susceptibility to transformation. Superficial GEM-PNST contained regions of nerve-associated plexiform neurofibromas or atypical neurofibromas and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulated nerve tumor progression in NF1 and provided preclinical platforms for testing therapies at each tumor grade. These results support a tumor progression model in which loss of NF1 in Schwann cells drives plexiform neurofibromas formation, additional loss of Ink4a/Arf contributes to atypical neurofibromas formation, and further changes underlie transformation to MPNST. SIGNIFICANCE: New mouse models recapitulate the stepwise progression of NF1 tumors and will be useful to define effective treatments that halt tumor growth and tumor progression in NF1.

| S-EPMC7968129 | biostudies-literature

Differential expression in wild-type and mutant neurofibroma and MPNST cell lines

Project description:Using RNA-seq we characterized gene expression changes occuring upon knockout of EZH2, EZH1, EZH1+EZH2 or SUZ12 in a neurofibroma cell line. We also investigated the transcriptional consequences of EZH1+EZH2 double knockout in a SUZ12-mutant MPNST cell line.

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Transgenic mice overexpressing Neuregulin-1 model neurofibroma-malignant peripheral nerve sheath tumor progression and implicate specific chromosomal copy number variations in tumorigenesis.

Project description:Patients with neurofibromatosis type 1 (NF1) develop benign plexiform neurofibromas that frequently progress to become malignant peripheral nerve sheath tumors (MPNSTs). A genetically engineered mouse model that accurately models plexiform neurofibroma-MPNST progression would facilitate the identification of somatic mutations driving this process. We have previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P0-GGF?3 mice) develop MPNSTs. To determine whether P0-GGF?3 mice accurately model neurofibroma-MPNST progression, cohorts of these animals were followed to death and necropsied. 94% of the mice developed multiple neurofibromas, with 70% carrying smaller numbers of MPNSTs; nascent MPNSTs were identified within neurofibromas, suggesting that these sarcomas arise from neurofibromas. Although neurofibromin expression was maintained, P0-GGF?3 MPNSTs, like human NF1-associated MPNSTs, demonstrated Ras hyperactivation. P0-GGF?3 MPNSTs also showed abnormalities in the p16INK4A-cyclin D/CDK4-Rb and p19ARF-Mdm-p53 pathways analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P0-GGF?3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 genes previously implicated in neoplasia (e.g., Pten, Tpd52, Myc , Gli1, Xiap, Bbc3/PUMA). Array CGH also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P0-GGF?3 mice represent a robust model of neurofibroma-MPNST progression that can be used to identify novel genes driving neurofibroma and MPNST pathogenesis. Array CGH comparison of malignant peripheral nerve sheath tumor (MPNST) cells vs non-neoplastic Schwann cells

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RNA-seq dataset for MPNST patient tissue samples

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Transcriptional programs dictating Schwann cell transformation in MPNST [scATACseq]

Project description:We used single-cell RNAseq to profile early and advanced mouse MPNST tumors, as well as human neurofibroma and MPNST. Our work defines the stage-specific kinetics of transcriptomics, cellular heterogeneity, and tumor cell fate decisions in murine and human MPNSTs.

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Transcriptional programs dictating Schwann cell transformation in MPNST [bulk RNA-seq]

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Direct comparison of Cdkn2a and p53 loss reveals global transcriptomic differences, including tumor suppressor dependency on pentose phosphate pathway in MPNST

Project description:Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor overall survival. Loss of tumor suppressors CDKN2A (~80%) or P53 (~20%) is a signature event in MPNST development. Here, we use CRISPR/Cas9 somatic tumorigenesis mouse models to mechanistically compare CDKN2A and P53 loss transcriptomic and metabolic differences, leading to therapeutic vulnerabilities in MPNSTs. Multi-omic analyses identified the pentose phosphate pathway (PPP) and regulation of NADPH metabolism as critical metabolic vulnerabilities in the CDKN2A-deleted MPNSTs. Disruption of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting step in the PPP, slowed CDKN2A-deleted MPNST growth, yet sensitized both genotypes of MPNSTs to standard-of-care chemotherapy. Moreover, the redox-regulated transcription factor NRF2 controlled G6PD activity in these tumors. Genomic analysis of patient samples showed a NRF2 gene signature that correlated with tumor transformation, further underscoring this pathway as a therapeutic target. This work identifies the G6PD/NADPH axis as a central metabolic vulnerability in MPNSTs.

2025-08-01 | GSE275277 | GEO

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