Ex Vivo Patient-Derived Explant Model for Neurofibromatosis Type 1–Related Cutaneous Neurofibromas

Abstract

Cutaneous neurofibromas (CNF) are benign tumors that occur in the dermis of individuals with the inherited tumor predisposition disorder, neurofibromatosis type 1 (NF). CNFs cause disfigurement, pain, burning, and itching, resulting in substantially reduced quality of life in NF patients. CNFs are benign tumors that exhibit cellular and molecular heterogeneity making it difficult to develop tractable in vitro or in vivo models. As a result, CNF research and drug discovery efforts have been limited. To address this need, we developed a reproducible patient derived explant (PDE) ex vivo culture model using CNF tumors from NF patients. CNF PDEs remain viable in culture for over 9 days and recapitulate the cellular composition and molecular signaling of CNFs. Using CNF PDEs as a model system, we found that proliferation was associated with increased T cell infiltration. Further, we identified a pattern of reciprocal inflammatory signaling in CNF PDEs in which tumors rely on prostaglandin or leukotriene mediated signaling pathways. As proof of principle, we show that ex vivo glucocorticoid treatment reduced expression of pro-inflammatory genes, confirming CNF PDEs are a useful model for both mechanistic studies and preclinical drug testing.