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Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression

ABSTRACT: Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression

PROVIDER: PRJNA697979 | ENA |

REPOSITORIES: ENA

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Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression

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

Effect of RRM2 knockdown on gene expression of NF1-associated MPNST cells

Project description:To investigate the role of RRM2 in the progression of NF1-associated MPNST, we established S462TY cell in which target gene has been knocked down by shRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of control and knockdown of target gene group

2022-09-26 | GSE213988 | GEO

Effect of p53 knockout on gene expression during capmatinib treatment of NF1-MET murine MPNST cells

Project description:To investigate the function of p53 in regulating response to MET inhibition in MPNST cells we established NF1-MET;sgP53 cells in which Trp53 was knocked out using CRISPR-Cas9. As a control, the parental NF1-MET was transduced with CRISPR-Cas9 in the absence of sgRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of the 2 different cells treated with either capmatinib or vehicle in duplicate.

2024-03-14 | GSE225747 | GEO

Cdkn2a loss in a model of neurofibroma demonstrates stepwise tumor progression to atypical neurofibroma and MPNST

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

Array-CGH of malignant peripheral nerve sheath tumors (MPNST)

Project description:Comparison of copy number changes in MPNST samples against benign neurofibromas in NF1 patients 24 MPNSTs and 3 NF samples were hybridised to the human 32K BAC tiling path array

2010-05-18 | E-GEOD-16041 | biostudies-arrayexpress

Array-CGH of malignant peripheral nerve sheath tumors (MPNST)

Project description:Comparison of copy number changes in MPNST samples against benign neurofibromas in NF1 patients

2009-05-20 | GSE16041 | GEO

Spatial gene expression profiling unveils immuno-oncogenic programs of NF1-associated peripheral nerve sheath tumor progression

Project description:Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) that arise in persons with neurofibromatosis type 1 (NF1). Despite similar histological appearance, these neoplasms proceed along diverse evolutionary trajectories, with a subset progressing to a devastating form of sarcoma called malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathological features and CDKN2A copy number loss. While genomic studies have improved our understanding of key driver events promoting tumor progression, the transcriptional alterations that precede malignant transformation remain poorly understood. Here we resolve gene expression profiles in PNSTs across the neurofibroma-to-MPNST continuum in NF1 patients and genetically engineered mouse models, providing insight into nascent molecular features associated with neurofibroma evolution and transformation. These findings highlight the need for molecular diagnostic tools that augment conventional histopathological criteria to identify neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.

2023-12-14 | GSE239561 | GEO

Unmasking Intra-tumoral Heterogeneity and Clonal Evolution in NF1-MPNST.

Project description: Not available

| S-EPMC7291009 | biostudies-literature

PRC2 is a tumor suppressor in malignant peripheral nerve sheath tumor (MPNST)

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.

2024-03-01 | GSE226980 | GEO

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumor

Project description:Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1 proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1 deficient cells, which identified 23 compounds capable of killing NF1 deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All trugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform has yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

2024-03-21 | GSE262030 | GEO

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