Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165826 | GEO | 2021/04/07
REPOSITORIES: GEO
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Project description:Understanding biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumors is essential, as tumor biomarkers, prognostic factors and therapeutics are all lacking. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (n = 22), malignant peripheral nerve sheath tumor (MPNST) cell lines (n = 13), benign neurofibromas (n = 26) and MPNST (n = 6). Dermal and plexiform neurofibromas were indistinguishable. A prominent theme in the analysis was aberrant differentiation. Neurofibromas repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes upregulated in the sarcomas were significantly enriched for genes activated in neural crest cells. We validated differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in neurofibroma and MPSNT tissue sections and targeting SOX9 - strongly expressed in NF1-related tumors - caused MPNST cell death. SOX9 is a biomarker of neurofibroma and MPNST, and possibly a therapeutic target in NF1. Keywords: tumor stage 86 microarrays, consisting of 77 samples and 9 batch reference samples: NHSC (10), dNFSC (11), pNFSC (11), MPNST cell lines (13), dNF (13), pNF (13), MPNST (6)
2009-07-15 | E-GEOD-14038 | biostudies-arrayexpress
Project description:Understanding biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumors is essential, as tumor biomarkers, prognostic factors and therapeutics are all lacking. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (n = 22), malignant peripheral nerve sheath tumor (MPNST) cell lines (n = 13), benign neurofibromas (n = 26) and MPNST (n = 6). Dermal and plexiform neurofibromas were indistinguishable. A prominent theme in the analysis was aberrant differentiation. Neurofibromas repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes upregulated in the sarcomas were significantly enriched for genes activated in neural crest cells. We validated differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in neurofibroma and MPSNT tissue sections and targeting SOX9 - strongly expressed in NF1-related tumors - caused MPNST cell death. SOX9 is a biomarker of neurofibroma and MPNST, and possibly a therapeutic target in NF1. Keywords: tumor stage
2009-07-15 | GSE14038 | GEO
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
Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials. 83 microarrays: Mouse control (15), Mouse neurofibroma (15), Mouse MPNST (18); Human nerve (3), Human neurofibroma (26), Human MPNST (6) We used the same human tumor samples as in series GSE14038 (dNF, pNF and MPNST). However, instead of referencing gene expression changes to the normal human Schwann cell samples (NHSC) as we did in series GSE14038, we generated three (new) normal nerve samples (samples jan-N1-3) and referenced gene expression changes to those samples. Moreover, the analysis of series GSE14038 evaluated changes in expression between NHSC, benign tumor subtypes (dNF and pNF), and malignant tumors (MPNST), while our present submission evaluated changes between normal nerve, benign tumors (combined dNF and pNF),and malignant tumors (MPNST). The Series supplementary 'merged_data.txt' file contains the data for 9,891 transcripts that were statistically different in at least one of the two species and present in both mouse and human data sets.
2012-12-28 | E-GEOD-41747 | biostudies-arrayexpress
Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.
2012-12-28 | GSE41747 | GEO
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:We devised a transgene that expresses in the neural crest lineage cells at embryonic stage day 13.5. The transgene has an inducible Cre cassette and was used to induce Trp53 and Nf1 gene recombination in the cells of dorsal root ganglia and boundary cap of nerve roots (DRG&BC) at E13.5. The malignant peripheral nerve sheath tumor (MPNST) allograft model was generated by sciatic nerve injection using the recombined E13.5 DRG&BC cells. The nuclear localized eGFP from the transgene was used to facilitate the florescence activated cell sorting (FACS) of GFP+ and GFP- tumor cells after removal of wildtype cells from the dissociated tumors, including immune cells, endothelia cells and blood cells. GFP+ and GFP- tumor cells were harvested from 5 different allograft MPNSTs. Total RNA were prepared from 10 samples were sequenced on Hiseq4000 sequencer. The data was to support the transgene-labeled cancer stem cell population in MPNST mouse models.
2021-01-31 | GSE152752 | GEO
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:Neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder, affecting 1 in 3,500 individuals worldwide and predisposing to cancer. Germline mutations in the NF1 gene, encoding the p21Ras GTPase-activating protein (GAP) neurofibromin, are the underlying cause for NF1. Somatic inactivation of the wild type copy of NF1 leads to deregulated Ras signaling. Clinical manifestations are diverse for NF1 patients, but the predominant lesions are plexiform neurofibroma (PNF), arising from the Schwann cell (SC) lineage. While PNF are generally benign, approximately 10% of patients will experience PN progression to highly aggressive malignant peripheral nerve sheath tumors (MPNST) with poor prognosis. There are currently no approved targeted therapies for PNF or MPNST. In this study, we used a conditional mouse model of NF1, test the multi-receptor tyrosine kinase inhibitor, cabozantinib (XL184). Mice were treated with vehicle or with cabozantinib for 3 or 7 days. Tissue was harvested, lysates prepared, and the lysate was used for kinome profiling. From cell lines or tumor tissue, protein lysates are prepared and passed over an affinity matrix consisting of Sepharose beads covalently coupled to a mixture of linker-adapted Type I kinase inhibitors. Kinase capture is reproducible and is a function of affinity for kinases for the immobilized inhibitors, expression level of the kinase, as well as the activation state of the kinase. Following affinity purification, kinases are identified and their multiplexed kinase inhibitor bead binding quantified by mass spectrometry (MIB/MS). Our goal is to identify the kinome changes in NF1 plexiform neurofibroma induced by cabozantinib treatment.
2023-05-18 | PXD019005 | Pride
Project description:Neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder, affecting 1 in 3,500 individuals worldwide and predisposing to cancer. Germline mutations in the NF1 gene, encoding the p21Ras GTPase-activating protein (GAP) neurofibromin, are the underlying cause for NF1. Somatic inactivation of the wild type copy of NF1 leads to deregulated Ras signaling. Clinical manifestations are diverse for NF1 patients, but the predominant lesions are plexiform neurofibroma (PNF), arising from the Schwann cell (SC) lineage. While PNF are generally benign, approximately 10% of patients will experience PN progression to highly aggressive malignant peripheral nerve sheath tumors (MPNST) with poor prognosis. There are currently no approved targeted therapies for PNF or MPNST. In this study, we used a conditional mouse model of NF1, test the multi-receptor tyrosine kinase inhibitor, cabozantinib (XL184). Mice were treated with vehicle or with cabozantinib for 3 or 7 days. Tissue was harvested, lysates prepared, and the lysate was used for kinome profiling. From cell lines or tumor tissue, protein lysates are prepared and passed over an affinity matrix consisting of Sepharose beads covalently coupled to a mixture of linker-adapted Type I kinase inhibitors. Kinase capture is reproducible and is a function of affinity for kinases for the immobilized inhibitors, expression level of the kinase, as well as the activation state of the kinase. Following affinity purification, kinases are identified and their multiplexed kinase inhibitor bead binding quantified by mass spectrometry (MIB/MS). Our goal is to identify the kinome changes in NF1 plexiform neurofibroma induced by cabozantinib treatment.
2020-11-19 | PXD019138 | Pride