Reciprocal inflammatory signaling in an ex-vivo explant model for neurofibromatosis type 1-related cutaneous neurofibromas

Abstract

Cutaneous neurofibromas (CNF) are benign tumors that occur in the dermis of individuals with neurofibromatosis type 1 (NF), an inherited tumor predisposition syndrome. CNFs cause disfigurement, pain, burning, and itching, resulting in reduced quality of life in NF patients. However, due to their benign nature there are few in vitro or in vivo models of CNFs, which has limited the research of CNF biology and drug discovery efforts. To address this, we developed a patient derived explant (PDE) ex vivo culture model of CNF tumors and normal skin from NF patients. CNF PDEs remain viable in culture for over 9 days and recapitulate the cellular composition and molecular signaling of CNFs. We identified reciprocal inflammatory signaling in CNF PDEs, in which tumors rely on either prostaglandin or leukotriene mediated signaling pathways. Ex vivo glucocorticoid treatment reduced expression of pro-inflammatory genes, confirming CNF PDEs are a useful model for mechanistic studies and preclinical drug testing.