Existing and Developing Preclinical Models for Neurofibromatosis Type 1LRelated Cutaneous Neurofibromas

Neurofibromatosis type 1 (NF1) is caused by a nonfunc-tional copy of the NF1 tumor suppressor gene that pre-disposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treat-ment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experi-mental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprece-dented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two-and three-dimensional cell cultures, organoids, genetically engi-neered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to hu-man cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.Journal of Investigative Dermatology (2023) 143, 1378-1387; doi:10.1016/ j.jid.2023.01.042