Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment

Area of Science:

• Oncology
• Genetics
• Cell Biology

Background:

• Neurofibromatosis 1 (NF1) is a genetic disorder causing benign nerve tumors called neurofibromas.
• These tumors arise from Schwann cells (SCs) with NF1 gene loss.

Purpose of the Study:

• To identify early cellular and molecular alterations during neurofibroma development in NF1.
• To understand the role of Schwann cells and associated stromal/immune cells in tumor formation.

Main Methods:

• Single-cell and bulk RNA sequencing of normal and neurofibroma Schwann cells (SCs).
• Comparative analysis of mouse and human neurofibroma samples.
• Cross-species analysis of cell populations and cell-cell communication.

Main Results:

• Identified five distinct SC populations in neurofibromas, including a novel SC progenitor-like (SCP-like) population.
• Observed PN-specific gene expression (Dcn, Postn, Cd74) and sustained injury response gene (Postn) expression in SCs.
• Detected significant expansion of immune and stromal cells (up to 90% in human PNs) and aberrant macrophage differentiation.

Conclusions:

• NF1 loss triggers profound changes in multiple SC types and promotes a tumor microenvironment rich in stromal and immune cells.
• Identified deregulated cell communication pathways (PROS1-AXL, FGF-FGFR, MIF-CD74/NF-κB) involving SCP-like cells.
• These findings suggest novel therapeutic targets for plexiform neurofibromas (PNs).