Dataset Information

Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas.

ABSTRACT: The tumor predisposition disorder neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system. It is caused by mutations in the Nf1 tumor-suppressor gene, which encodes a GTPase-activating protein (GAP) that negatively regulates p21-RAS. Development of malignant nerve tumors and neurofibromas occurs frequently in NF1. However, little is known about the molecular mechanisms mediating the initiation and progression of these complex tumors, or the identity of the specific cell type that gives rise to dermal or cutaneous neurofibromas. In this study, we identify a population of stem/progenitor cells residing in the dermis termed skin-derived precursors (SKPs) that, through loss of Nf1, form neurofibromas. We propose that SKPs, or their derivatives, are the cell of origin of dermal neurofibroma. We also provide evidence that additional signals from nonneoplastic cells in the tumor microenvironment play essential roles in neurofibromagenesis.

SUBMITTER: Le LQ

PROVIDER: S-EPMC2737469 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas.

Le Lu Q LQ Shipman Tracey T Burns Dennis K DK Parada Luis F LF

Cell stem cell 20090501 5

The tumor predisposition disorder neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system. It is caused by mutations in the Nf1 tumor-suppressor gene, which encodes a GTPase-activating protein (GAP) that negatively regulates p21-RAS. Development of malignant nerve tumors and neurofibromas occurs frequently in NF1. However, little is known about the molecular mechanisms mediating the initiation and progression of these complex tumors, or the identity of th ...[more]

PMID: 19427294

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Project description:Plexiform neurofibroma (PN) are a leading cause of morbidity in Neurofibromatosis Type 1 (NF1), often disfiguring or threatening vital structures. During formation of PN, a complex tumor microenvironment (TME) develops, with recruitment of neoplastic and non-neoplastic cell types being critical for growth and progression. Due to the cohesive cellularity of PN, single-cell RNA-sequencing is difficult and may result in a loss of detection of critical cellular subpopulations, therefor single-nuclei RNA-sequencing (snRNA-seq) was applied retrospectively to 8 frozen PN, a large enough sample cohort required to adequately describe the disease TME. Additionally, 4 frozen PN samples were OCT embedded and spatial transcriptomics (ST) was run, adding morphological context to the transcriptomic data generated. Our snRNA-seq analysis definitively charted the heterogeneous cellular subpopulations in the PN TME, with the predominant fraction being fibroblast-like cells. PN have a remarkable amount of inter-sample homogeneity regarding cellular subpopulation proportions despite being resected from a variety of anatomical locations. ST analysis identified distinct cellular subpopulations which were annotated using snRNA-seq data that correlated with histological features. Schwann cell/fibroblast interactions were further characterized by receptor/ligand interaction analysis (CellChat) that was applied to snRNA-seq data. A high probability of Neurexin 1/Neuroligin 1 (NRXN1/NRGLN1) receptor-ligand crosstalk was predicted between non-myelinated Schwann cells (NM_SC) and fibroblast subpopulations, respectively. We observed aberrant expression of NRXN1 and NRGLN1 in our snRNA-seq data versus normal mouse sciatic nerve. This pathway has never been described in PN but has been observed in other NF1-associated tumors and may indicate a clear and direct communication pathway between putative NM_SC cells of origin and surrounding fibroblasts, potentially driving disease progression. SnRNA-seq integrated with spatial transcriptomics advances our understanding of the complex cellular heterogeneity of PN. These data identify potential novel communication pathways that may drive disease progression, a finding that could provide translational therapy options for patients with these devastating tumors of childhood and early adulthood.

Project description:Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time; for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0-8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDR<0.01) and seven trending (0.01⩽FDR<0.02) gene sets related to DNA replication, telomere maintenance and elongation, cell cycle progression, signal transduction and cell proliferation. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.

Dataset Information

Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas.

Publications

Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas.

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