NF1-Associated Peripheral Nerve Sheath Tumors at Single Cell Resolution: Heterogeneity, Tumor Growth, and MalignantProgression

reportActive / Technical Report | Accesssion Number: AD1212030 | Open PDF

Abstract:

The development of tumors of the peripheral nervous system (PNS) represents a major problem for persons with Neurofibromatosis type 1. Plexiform neurofibromas (pNFs) constitute a major source of morbidity. pNFs arise during development through the inactivation of the NF1 gene in a cell of the neural crest (NC) - Schwann cell (SC) lineage. In some cases, pNFs may undergo malignant transformation towards an aggressive and highly metastatic Malignant Peripheral Nerve Sheath Tumor (MPNST), normally through the previous development of a premalignant nodule termed atypical neurofibroma (aNF). Genomic analyses of pNF-aNF-MPNSTprogressions have demonstrated that these tumors share the same somatic NF1 inactivation, linking their cells of origin. We dont know whether within pNFs there are remaining cells with the same biological properties as the originating pNF cell, and if so, which role they might play in pNF growth, tumor progression or response to treatment. Our preliminary single cell RNA-seq data from different pNFs confirmed the diversity of cell types present in pNFs,and revealed the existence of cell subpopulations within specific cell type components, a previously unnoticed heterogeneity. The pNF SC component seems to contain at least two distinct groups of SCs, one expressing exclusively markers of precursor SCs (SCPs) and another group expressing in addition markers of SC commitment. There is also heterogeneity in the endoneurial fibroblast-like stromal (FB) component, with some subpopulations expressingkey mesenchymal transcription factors also identified in MPNST cells. The FB component mightplay an important role in pNF growth. We have recently generated human neurofibroma-like tumors in mice by engrafting 3D spheroids in their sciatic nerve. Only when these spheroids contain NF1(-/-) iPSC-derived differentiating SCs plus primary endoneurial FBs neurofibroma like tumors consistently develop.

Author(s):
Serra, Eduard ; Gel, Bernat ; Carrio, Meritxell
Author Organization(s):
Germans Trias i Pujol Research Institute (IGTP)
Funding Organization(s):
ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND FORT DETRICK MD, FORT DETRICK, MD
Document Type:
Technical Report/Annual Report
Publication Date:
2023 Jul 01
Pagination:
32

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DOCUMENT & CONTEXTUAL SUMMARY

Distribution Code:
A - Approved For Public Release
Distribution Statement: Public Release.
Copyright: Not Copyrighted

RECORD

Collection: TRECMS
Subject Terms
Descriptor(s):
peripheral nervous system, cells, biomedical research, gene expression, nervous system, neuromuscular diseases, spatial distribution, embryos, neoplasms, neuroglia, cellular structures, data analysis, transcriptomics, nerve tissue, nerves, cell line, fibroblasts
Keyword(s):
Plexiform neurofibroma, atypical neurofibroma, mpnst(malignant peripheral nerve sheath tumor), nerve, Schwann cell; fibroblast, cell-of-origin, cell heterogeneity, single cell analysis, genomics, bioinformatics, BIOMEDICAL INFORMATION SYSTEMS
Subject Categories:
Biological and Medical Sciences
Descriptor(s):
peripheral nervous system, neuromuscular diseases, biomedical research, nervous system, department of defense, sciatic nerve, neoplasms, nerves, cells, data analysis, maryland, nerve tissue, spatial distribution, embryos, heterogeneity, information operations
Creation Date:
2023 Oct 03
Update Date:
2023 Oct 27