Cellular Origin, Tumor Progression, and Pathogenic Mechanisms of Cutaneous Neurofibromas Revealed by Mice withNf1Knockout in Boundary Cap Cells

Abstract

Patients carrying an inactive NF1 allele develop tumors of Schwann cell origin called neurofi bromas (NF). Genetically engineered mouse models have signifi cantly enriched our understanding of plexiform forms of NFs (pNF). However, this has not been the case for cutaneous neurofi bromas (cNF), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fi d e pNFs and cNFs. This work identifi es subepidermal glia as a likely candidate for the cellular origin of cNFs and provides insights on disease mechanisms, revealing a long, multistep pathologic process in which infl ammation-related signals play a pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofi bromas. SIGNIFICANCE: Patients affected by NF1 develop numerous cNFs. We present a mouse model that faithfully recapitulates cNFs, identify a candidate cell type at their origin, analyze the steps involved in their formation, and show that their development is dramatically accelerated by skin injury. These fi ndings have important clinical/therapeutic implications.

The evolution and multi-molecular properties of NF1 cutaneous neurofibromas originating from C-fiber sensory endings and terminal Schwann cells at normal sites of sensory terminations in the skin

“…Our reassessment, herein, revealed pre-cNF-like lesions in the skin of these mice that were located at various adnexa where the pre-cNF were discovered in our human NF1 patients. A recently developed BCC selective Nf1 DI mouse model produced more obvious human-like cNF as well as pNFs [117]. This suggests that the hyperproliferating SC and likely TGFβ1-positive SC precursors in the pre-cNF and s-cNF in our NF1 patients arise de novo exclusively among the BCC-derived terminal SC.…”

Characterizing the Metabolic and Immune Landscape of Non-small Cell Lung Cancer Reveals Prognostic Biomarkers Through Omics Data Integration

“…Tumors are formed when normal cells continue to proliferate in an uncontrolled manner due to the loss of cell cycle control ( Radomska et al, 2019 ). Tumors develop different directions of mutations and malignant evolution due to different cancer-causing agents.…”

Schwann cell plasticity‐roles in tissue homeostasis, regeneration, and disease

“…Moreover, they produce, in separate waves of genesis, almost all SCs within the dorsal and ventral nerve roots, SGCs in dorsal root ganglia and a substantial number of SCs within the skin. In contrast, peripheral nerve trunk SCs are predominantly derived directly from neural crest cells (Gresset et al, ; Maro et al, ; Radomska et al, ; Radomska & Topilko, ). Interestingly, boundary cap cells not only differentiate into neuronal and glial cells within the PNS, they also retain the capacity to differentiate into OLs, astrocytes and neurons when exposed to signals of the developing CNS, highlighting the plasticity of this progenitor population (Zujovic et al, ).…”