Project description:Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma. Comprehensive proteomic profiles of 23 MPNST tumor specimens were obtained using LC-MS/MS. Among 23 tumor specimens, 13 patients showed favorable prognosis and 10 did local recurrence/distant metastasis.
Project description:PRC2 loss of function occurs frequently in human MPNST. Here, we found that PRC2-loss tumors are separated from PRC2-wt ones at the transcriptome level by RNA-seq among 41 human MPNST tumor tissues.
Project description:Using mouse models, we show that PRC2 restrains MPNST development in the peripheral nervous system in the absence of both Nf1 and Cdkn2a tumor suppressor genes. Here we conducted bulk RNA-sequencing of tumors generated in mice.
Project description:PRC2-isogenic human malignant peripheral nerve sheath tumor (MPNST) M3 cells were generated through CRISPR/Cas9-mediated knockout of the PRC2 core component, SUZ12. PRC2 loss leads to global loss of H3K27me3, which causes H3K27ac redistribution and also affect other histone modification, e.g., H3K36me2/3.
Project description:The diagnosis of Malignant peripheral nerve sheath tumors (MPNSTs) can be challenging, but is aided by their characteristic DNA methylation profile (DMP). An MPNST-like group, characterized by retained H3K27me3 expression, was recently recognized. To evaluate the diagnostic usefulness of DMP in pediatric/juvenile MPNSTs, we selected pediatric/juvenile malignancies from the Bambino Gesù Children's Hospital DMP database. DMP revealed unexpected molecular heterogeneity in histologically homogenous MPNSTs/Atypical neurofibromas, while samples with MPNST-like DMP manifested histological diversity. In conclusion, DMP is useful in diagnosing MPNST, discriminating morphologic mimics classified as MPNST in premolecular era, and investigating the MPNST-like ‘hybrid’ group in pediatrics.
Project description:The project aimed at determining whether the Polycomb complex PRC2 has a unique composition in androgen independent prostate cancer cells and the project aimed at determining whether EZH2, the enzymatic subunit of PRC2, retains any functional role in the context of Malignant peripheral nerve sheath tumor (MPNST) where either EED or SUZ12, two essential subunits of PRC2 are inactivated.
Project description:PRC2-isogenic human malignant peripheral nerve sheath tumor (MPNST) M3 cells were generated through CRISPR/Cas9-mediated knockout of the PRC2 core component, SUZ12. PRC2 loss led to not only significant increase, but also significant decrease of chromatin accessibility at 15,346 (16% of all ATAC peaks) and 20,099 genomic loci (21% of all ATAC peaks), respectively. PRC2 loss decreased the chromatin accessibility for IFNγ-responsive loci in M3 cells, resulting in dampened response to IFNγ stimulation.
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
Project description:Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. By characterizing recurrent gene copy number aberrations, we gain insight into the most altered pathways with the purpose of scanning possible therapeutic targets. We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. All samples had at least 90% tumor content. Commercially available normal genomic DNAs were used as control.