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

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.

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Document Details

Document Type
Technical Report
Publication Date
Jul 01, 2023
Accession Number
AD1212030

Entities

People

  • Bernat Gel
  • Eduard Serra
  • Meritxell Carrio

Organizations

  • Germans Trias i Pujol Research Institute

Tags

DTIC Thesaurus Topics

  • Biomedical Research
  • Cell Line
  • Cells
  • Cellular Structures
  • Data Analysis
  • Department Of Defense
  • Embryos
  • Fibroblasts
  • Gene Expression
  • Heterogeneity
  • Information Operations
  • Maryland
  • Neoplasms
  • Nerve Tissue
  • Nerves
  • Nervous System
  • Neuroglia
  • Neuromuscular Diseases
  • Peripheral Nervous System
  • Sciatic Nerve
  • Spatial Distribution
  • Transcriptomics

Fields of Study

  • Biology

Readers

  • Molecular and Cellular Biology
  • Molecular and genetic basis of cancer.
  • Oncology (Cancer Research).