Molecular characterization of a series of 7 NF1-associated human MPNSTs
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE92647 | GEO | 2016/12/21
SECONDARY ACCESSION(S): PRJNA358225
REPOSITORIES: GEO
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Project description:22 plexiform neurofibromas from 18 unrelated neurofibromatosis-type 1 patients were screened with a high resolution array-CGH. Each PNF DNA (somatic tumor DNA) was individually hybridized on Agilent whole human genome 244K microarrays (Platform GPL4091) using the matched genomic constitutional DNA (lymphocytes DNA) from the corresponding patient as reference, in order to detect tumor-specific aberrations.
2011-09-30 | GSE24328 | GEO
Project description:22 plexiform neurofibromas from 18 unrelated neurofibromatosis-type 1 patients were screened with a high resolution array-CGH. Each PNF DNA (somatic tumor DNA) was individually hybridized on Agilent whole human genome 244K microarrays (Platform GPL4091) using the matched genomic constitutional DNA (lymphocytes DNA) from the corresponding patient as reference, in order to detect tumor-specific aberrations. NF1-associated plexiform neurofibromas DNA vs. constitutional DNA
2011-09-29 | E-GEOD-24328 | biostudies-arrayexpress
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an NF1 MPNST patient derived xenograft model (PDX4) treated with SHP099, hydroxychloroquine (HCQ) or the combination. Kinase enrichment proteomic analysis was performed using tumor tissue treated with SHP099, hydroxychloroquine (HCQ) or the combination to evaluate the effects on the functional kinome.
2024-11-20 | PXD036000 | Pride
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.
2024-12-12 | GSE283902 | GEO
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an orthotopic implantation murine model of NF1 MPNST with defined gentotype (NI, Nf1-/-;Ink4a/Arf-/-). Kinase enrichment proteomic analysis was performed using tumor tissue from vehicle, SHP099, or trametinib and SHP099 in combination for 5, 15, or 28 days to evaluate the effects on the functional kinome.
2024-11-20 | PXD035998 | Pride
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an orthotopic implantation murine model of NF1 MPNST with defined genotype (NP, Nf1-/-;Trp53-/-). Kinase enrichment proteomic analysis was performed using tumor tissue from vehicle, SHP099, trametinib, or trametinib and SHP099 in combination for 5 or 21 days to evaluate the effects on the functional kinome.
2024-11-20 | PXD035999 | Pride
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
2012-12-31 | E-GEOD-40212 | biostudies-arrayexpress
Project description:Background: Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. Methods: We generated five patient-derived MPNST orthoxenograft models (three NF1-related and two sporadic) and performed an exhaustive histological and molecular characterization of primary MPNSTs and their corresponding orthoxenografts. Finally, orthoxenografts models were used as an in vivo pre-clinical platform to test several treatment strategies. Results: MPNST orthoxenografts recapitulate the histopathological properties and preserve the genomic and transcriptomic status of their parental primary tumors. Additionally, they mimic distal dissemination properties in mice. Compatible with an origin in a catastrophic event and subsequent stabilization, MPNSTs contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Although preliminary, the results presented here point to clear differences between NF1-associated and sporadic MPNSTs. In accordance, mutation frequency in sporadic MPNSTs was an order of magnitude higher than in NF1-associated MPNSTs and unsupervised cluster analysis and principal component analysis (PCA) using a MPNST signature perfectly divided the samples between NF1 and sporadic MPNST. Finally, different therapeutic approaches tested in the validated orthoxenograft MPNST models, reveal that sorafenib, or in combination with doxorubicin or rapamycin caused a great tumor reduction in all models. Conclusion: The development of a well-characterized and standardized preclinical model for MPNSTs has laid the foundations for evaluating novel therapeutic strategies in the clinical setting. Moreover, results obtained strongly support the clinical evaluation of Sorafenib in this subset of patients. Primary MPNSTs were implanted in the sciatic nerve of nude mices to create orthoxenograft MPNST models. Several orthoxenograft passages were created. The primary tumor (when available) and passages 1 and 4 were selected for gene expression profiling to demonstrate that the orthoxenografts closely resemble their primary tumors and are stable along xenograft passages.
2015-04-15 | E-GEOD-60082 | biostudies-arrayexpress
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Transformation from Nf1-null benign plexiform neurofibromas is driven by the loss of the Cdkn2a (Arf) locus. Here, genetically engineered mouse models with combined Nf1 flox/flox and Arf flox/flox alleles were used (crossed with Postn-Cre+ mice). Tissue from MPNSTs that form in the Nf1-/-;Arf-/- setting were used for mRNA sequencing and compared to benign plexiform neurofibroma tissue (Nf1-/- from Nf1 flox/flox; Postn-Cre+ mice, GSE213789) to identify transcriptome signatures from MPNST and compare them to benign plexiform neurofibroma.
2023-12-12 | GSE232707 | GEO
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.
2021-04-07 | GSE165826 | GEO