Project description:The goal of this experiment was to compare the genes expressed in malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of homozygous mutation of the p53 gene or heterozygous mutation of several different ribosomal protein (rp) mutations. Since MPNSTs arise very rarely in wild type zebrafish, it seemed a possibility that p53 and rps may in fact be functioning in similar pathways. The tumors arising from the different mutations had been previously classified as similar by histology, thus the goal of the array experiments was to establish if any molecular signatures could be found that could delineate the p53 from the rp MPNSTs. Keywords: Zebrafish malignant peripheral nerve sheath tumors from different genetic backgrounds
Project description:We used single-cell RNA-sequencing (scRNA-seq) to study the effect of ionizing radiation on the transcriptomes of malignant peripheral nerve sheath tumors (MPNSTs) in vivo and in the context of the innate and adaptive immune response.
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin dependent kinases (CDKs), commonly through loss of CDK inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs.
Project description:The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. Accordingly, we found less than one third of the human CNA genes were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers. --- This filing comprises data related to GEO entry GSE23666 ("Highly Aneuploid Zebrafish Malignant Peripheral Nerve Sheath Tumors have Genetic Alterations Similar to Human Cancers"), representing a followup study. 147 pairs of zebrafish (Danio rerio) tumor (MPNST) and normal tail control samples
Project description:The clinical significance of specific genetic alterations, methylation signatures or microenvironmental composition in malignant peripheral nerve sheath tumors (MPNSTs) is unclear. We assembled an updated cohort of 30 patients with MPNSTs treated with surgical resection and postoperative radiation who underwent methylation profiling and detailed clinical follow-up. The data included in this submission include 7 of 30 samples, the remainder of which were submitted separately under GSE212963.
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:mTOR and HDAC inhibitors induce cell death of malignant peripheral nerve sheath tumors (MPNSTs) in vitro, and in vivo We performed microarray analysis of mTOR and HDAC inhibition alone and in combination 24 hours after treatment, prior to induction of cell death, to identify transcriptional changes that might be mechanistic drivers of the therapeutic efficacy
Project description:The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. Accordingly, we found less than one third of the human CNA genes were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers. --- This filing comprises data related to GEO entry GSE23666 ("Highly Aneuploid Zebrafish Malignant Peripheral Nerve Sheath Tumors have Genetic Alterations Similar to Human Cancers"), representing a followup study.
