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:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with currently no effective treatment. While half of MPNSTs arise sporadically, the others are due to the malignant progression of neurofibromas (NFs) in patients with neurofibromatosis type 1 (NF1). NFs are benign nerve sheath tumors due to bi-allelic loss of NF1, encoding a negative regulator of Ras pathway, in the Schwann cell (SC) lineage. We have conceived an Nf1-KO mouse model in which NFs spontaneously transform into MPNSTs To decipher the step-by-step evolution of the cellular composition and biological activities of tumor cells and their microenvironment during the transformation process, we performed single-cell transcriptomic profiling of pNFs, dyNFs and MPNSTs, all issued from Prss56Cre, Nf1fl/fl cohort, using 10x Chromium platform. We discovered that malignant transformation is initiated by a molecular transition of tumor SCs from glial to mesenchymal identity (GMT).
Project description:Neurofibromatosis type 1 (NF1) is characterized by the development of benign nerve sheath tumors named plexiform neurofibromas (PNFs). In 10–15% of patients, these tumors undergo malignant transformation into aggressive malignant peripheral nerve sheath tumors (MPNSTs), which are associated with poor prognosis and limited treatment options. The cellular and molecular mechanisms driving this malignant progression remain poorly understood, hindering the development of effective therapies. To address this gap, we performed comprehensive single cell RNA sequencing on 9 PNF and 5 MPNST clinical samples.
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.
