EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation

Area of Science:

• Oncology
• Genetics
• Cell Biology

Background:

• Neurofibromatosis type 1 (NF1) is an inherited disorder predisposing patients to neurofibromas, which are benign Schwann cell (SC) tumors.
• Loss of Nf1 in mouse SCs recapitulates neurofibroma formation.
• Schwann cell precursors (SCPs) express Epidermal Growth Factor Receptor (EGFR) and are implicated in plexiform neurofibroma initiation.

Purpose of the Study:

• To investigate the role of EGFR activity in the initiation, size, and number of neurofibromas.
• To determine the mechanistic link between EGFR signaling and neurofibroma development.

Main Methods:

• Studied mice engineered to express human EGFR in SCs and SCPs, in the context of NF1 mouse models.
• Utilized gain- and loss-of-function assays for EGFR signaling.
• Performed in vivo transplantation experiments.
• Assessed cell self-renewal and STAT3 phosphorylation (P-Stat3) as surrogates for tumor initiation and signaling pathway activation.

Main Results:

• Increased neurofibroma number and size in mice with elevated EGFR expression.
• Decreased neurofibroma number in mice with diminished EGFR signaling.
• EGFR activation enhanced SCP/neurofibroma-initiating cell self-renewal and P-Stat3.
• Interleukin-6 (Il-6) reinforced Jak2/Stat3 activation in SCPs and SCs.

Conclusions:

• EGFR signaling levels in SCPs critically modulate neurofibroma initiation.
• EGFR activity is a key factor in the development of NF1-associated tumors.