A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Abstract

Skin is the calling card of humanity—the body’s first line of defense against external threats and a major part of a person’s identity. Diseases of the skin are common and a leading cause of nonfatal disease burden in humans (Hay et al., 2014Hay R.J. Johns N.E. Williams H.C. Bolliger I.W. Dellavalle R.P. Margolis D.J. et al.The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions.J Invest Dermatol. 2014; 134: 1527-1534Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Effectively addressing skin diseases not only halts or prevents physical illness, it often treats or prevents the common comorbidities of skin disease: depression, anxiety, and suicidal ideation (Hay et al., 2014Hay R.J. Johns N.E. Williams H.C. Bolliger I.W. Dellavalle R.P. Margolis D.J. et al.The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions.J Invest Dermatol. 2014; 134: 1527-1534Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Misery et al., 2018Misery L. Seneschal J. Reguiai Z. Merhand S. Héas S. Huet F. et al.Patient burden is associated with alterations in quality of life in adult patients with atopic dermatitis: results from the ECLA study.Acta Derm Venereol. 2018; 98: 713-714Crossref Scopus (18) Google Scholar). Such mental health diagnoses carry their own substantial disease burden and dramatically impact QOL for both the person and the community affected by chronic skin diseases (Dalgard et al., 2015Dalgard F.J. Gieler U. Tomas-Aragones L. Lien L. Poot F. Jemec G.B.E. et al.The psychological burden of skin diseases: A cross-sectional multicenter study among dermatological out-patients in 13 European countries.J Invest Dermatol. 2015; 135: 984-991Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). Accordingly, an important aspect of effectively treating or preventing skin disease is improving mental health comorbidities and QOL through therapeutic discovery (Kaundinya et al., 2022Kaundinya T. Rakita U. Guraya A. Abboud D.M. Croce E. Thyssen J.P. et al.Differences in psychometric properties of clinician- and patient-reported outcome measures for atopic dermatitis by race and skin tone: A systematic review.J Invest Dermatol. 2022; 142: 364-381Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Renert-Yuval et al., 2022Renert-Yuval Y. Correa da Rosa J. Garcet S. Pavel A.B. Bares J. Chima M. et al.Analysis of alopecia areata surveys suggests a threshold for improved patient-reported outcomes.Br J Dermatol. 2022; 187: 539-547Crossref Scopus (4) Google Scholar). Of course, to achieve that critical step, we must first understand disease pathophysiology, develop therapies on the basis of established biologic mechanisms, know the natural history of the disease, and validate meaningful outcome measures for therapeutic interventions. Successful generation of this enormous dataset can result in incredible benefits for people living with skin disease. Indeed, there has been a recent explosion of new drug therapies (including a raft of new biologic agents targeting specific mediators of disease pathobiology) for conditions such as atopic dermatitis, psoriasis, and vitiligo (Arkwright and Koplin, 2023Arkwright P.D. Koplin J.J. Impact of a decade of research into atopic dermatitis.J Allergy Clin Immunol Pract. 2023; 11: 63-71Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar; Chovatiya and Paller, 2021Chovatiya R. Paller A.S. JAK inhibitors in the treatment of atopic dermatitis.J Allergy Clin Immunol. 2021; 148: 927-940Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Malik and Guttman-Yassky, 2018Malik K. Guttman-Yassky E. Cytokine targeted therapeutics for alopecia areata: lessons from atopic dermatitis and other inflammatory skin diseases.J Investig Dermatol Symp Proc. 2018; 19: S62-S64Abstract Full Text Full Text PDF PubMed Google Scholar). Such developments give inspiration and direction for another skin condition that has been without therapeutic advance: cutaneous neurofibromas (cNFs). cNFs are the most common tumor in people with the autosomal dominant neurocutaneous condition, neurofibromatosis type 1 (NF1) (Guiraud et al., 2019Guiraud M. Bouroubi A. Beauchamp R. Bocquet A. Grégoire J.M. Rauly-Lestienne I. et al.Cutaneous neurofibromas: patients' medical burden, current management and therapeutic expectations: results from an online European patient community survey.Orphanet J Rare Dis. 2019; 14: 286Crossref PubMed Scopus (9) Google Scholar). Nearly all adults with NF1 are afflicted with cNFs ranging in number from a handful to several thousand tumors involving the skin of all regions of the body (Cannon et al., 2018Cannon A. Chen M.J. Li P. Boyd K.P. Theos A. Redden D.T. et al.Cutaneous neurofibromas in neurofibromatosis type I: A quantitative natural history study.Orphanet J Rare Dis. 2018; 13: 31Crossref PubMed Scopus (28) Google Scholar; Ehara et al., 2018Ehara Y. Yamamoto O. Kosaki K. Yoshida Y. Natural course and characteristics of cutaneous neurofibromas in neurofibromatosis 1.J Dermatol. 2018; 45: 53-57Crossref PubMed Scopus (14) Google Scholar). cNFs are intermittently painful and itchy and can compromise skin integrity. In all cases, cNFs are disfiguring, negatively impacting mental health and QOL (Guiraud et al., 2019Guiraud M. Bouroubi A. Beauchamp R. Bocquet A. Grégoire J.M. Rauly-Lestienne I. et al.Cutaneous neurofibromas: patients' medical burden, current management and therapeutic expectations: results from an online European patient community survey.Orphanet J Rare Dis. 2019; 14: 286Crossref PubMed Scopus (9) Google Scholar; Maguiness et al., 2021Maguiness S. Berman Y. Rubin N. Dodds M. Plotkin S.R. Wong C. et al.Measuring the effect of cutaneous neurofibromas on quality of life in neurofibromatosis type 1.Neurology. 2021; 97: S25-S31Crossref PubMed Scopus (1) Google Scholar). NF1 is the most common autosomal dominant neurocutaneous disease (estimated incidence of 1:3,000), and nearly 100% (roughly 2.5 million people worldwide) develop cNFs. Indeed, people living with NF1 report that cNFs are the manifestation that they find most distressing (Guiraud et al., 2019Guiraud M. Bouroubi A. Beauchamp R. Bocquet A. Grégoire J.M. Rauly-Lestienne I. et al.Cutaneous neurofibromas: patients' medical burden, current management and therapeutic expectations: results from an online European patient community survey.Orphanet J Rare Dis. 2019; 14: 286Crossref PubMed Scopus (9) Google Scholar; Maguiness et al., 2021Maguiness S. Berman Y. Rubin N. Dodds M. Plotkin S.R. Wong C. et al.Measuring the effect of cutaneous neurofibromas on quality of life in neurofibromatosis type 1.Neurology. 2021; 97: S25-S31Crossref PubMed Scopus (1) Google Scholar). Yet, historically, there has been a lack of dedicated effort to understand the pathophysiology, relevant preclinical and clinical endpoints, and potential therapies to prevent and treat cNFs. A committed effort to understanding and effectively treating NF1-associated cNFs will benefit not only people with NF1 but all people with dermal lesions that are associated with neuropathic irritation, itch, and disfigurement because the core elements of cNFs (Schwann cells, fibroblasts, mast cells, and macrophages) are shared across many skin conditions. The time is optimal for multidisciplinary investment in unraveling the elemental factors that contribute to cNF formation, their associated symptoms, and the many opportunities to prevent and treat these tumors and their comorbidities. The articles presented in this “Spotlight on Cutaneous Neurofibroma” reflect the work undertaken by a community of invested stakeholders (patients and caregivers, basic scientists, clinical scientists, dermatologists, neuro-oncologists, and regulatory experts) to explore key questions pertaining to developing effective therapeutics for cNFs in people with NF1. Individuals with expertise in various areas participated in the 2022 cNF symposium organized by the Neurofibromatosis Therapeutic Acceleration Program. Four teams focused on addressing core concepts in cNF Pathology and Biology, Therapeutic Targets for cNF Treatment, Preclinical Testing and Assays, and Human Clinical Trials: Therapeutic Strategy and Development. Through a review of published and unpublished data and leveraging the recent therapeutic advances for other NF1-associated tumors such as plexiform neurofibromas (pNFs) and optic pathway gliomas (Fangusaro et al., 2021Fangusaro J. Onar-Thomas A. Poussaint T.Y. Wu S. Ligon A.H. Lindeman N. et al.A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: A pediatric brain tumor consortium study.Neuro Oncol. 2021; 23: 1777-1788Crossref PubMed Scopus (0) Google Scholar; Gross et al., 2020Gross A.M. Wolters P.L. Dombi E. Baldwin A. Whitcomb P. Fisher M.J. et al.Selumetinib in children with inoperable plexiform neurofibromas.N Engl J Med. 2020; 382 ([published correction appears in N Eng J Med 2020;383:1290]): 1430-1442Crossref PubMed Scopus (243) Google Scholar) and positive outcomes for other skin conditions such as vitiligo and alopecia areata that were previously without meaningful therapeutic advance (Chovatiya and Paller, 2021Chovatiya R. Paller A.S. JAK inhibitors in the treatment of atopic dermatitis.J Allergy Clin Immunol. 2021; 148: 927-940Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Sheikh et al., 2022Sheikh A. Rafique W. Owais R. Malik F. Ali E. FDA approves Ruxolitinib (opzelura) for vitiligo therapy: A breakthrough in the field of dermatology.Ann Med Surg (Lond). 2022; 81104499Google Scholar), the teams addressed what is known as well as the knowledge gaps needing to be filled to support meaningful therapeutic development for NF1-associated cNFs. NF1 results from inactivating pathogenic variants in the NF1 gene, which is located on chromosome 17q11.2 (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar; Carey et al., 1986Carey J.C. Baty B.J. Johnson J.P. Morrison T. Skolnick M. Kivlin J. The genetic aspects of neurofibromatosis.Ann N Y Acad Sci. 1986; 486: 45-56Crossref PubMed Google Scholar; Upadhyaya et al., 1997Upadhyaya M. Osborn M.J. Maynard J. Kim M.R. Tamanoi F. Cooper D.N. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene.Hum Genet. 1997; 99: 88-92Crossref PubMed Scopus (90) Google Scholar). The gene product, neurofibromin, is widely expressed in almost all tissues but is most abundant in the central and peripheral nervous systems (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar; Daston and Ratner, 1992Daston M.M. Ratner N. Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitously expressed during development.Dev Dyn. 1992; 195: 216-226Crossref PubMed Google Scholar; Upadhyaya et al., 1997Upadhyaya M. Osborn M.J. Maynard J. Kim M.R. Tamanoi F. Cooper D.N. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene.Hum Genet. 1997; 99: 88-92Crossref PubMed Scopus (90) Google Scholar). NF1 can result from a de novo or familial pathogenic variant and is transmitted in an autosomal dominant inheritance pattern. Roughly 50% of patients with NF1 have a spontaneous pathogenic variant since the NF1 gene has one of the highest rates of spontaneous variation (Carey et al., 1986Carey J.C. Baty B.J. Johnson J.P. Morrison T. Skolnick M. Kivlin J. The genetic aspects of neurofibromatosis.Ann N Y Acad Sci. 1986; 486: 45-56Crossref PubMed Google Scholar). Absence of functional neurofibromin contributes to the constitutive activation of RAS (Bollag et al., 1996Bollag G. Clapp D.W. Shih S. Adler F. Zhang Y.Y. Thompson P. et al.Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.Nat Genet. 1996; 12: 144-148Crossref PubMed Scopus (481) Google Scholar). RAS is a commonly mutated oncogene that is implicated in most human cancers. Altered RAS regulation is also associated with a range of conditions affecting multiple organs termed the RASopathies (Matthews et al., 2022Matthews H. Vanneste M. Katsura K. Aponte D. Patton M. Hammond P. et al.Refining nosology by modelling variation among facial phenotypes: the RASopathies [epub ahead of print].J Med Genet. 2022; (accessed XXX)https://doi.org/10.1136/jmedgenet-2021-108366Crossref Scopus (1) Google Scholar). NF1 is one such Rasopathy because variants in the gene NF1 lead to reduced function of neurofibromin and dysregulation of RAS. This results in highly variable clinical manifestations ranging from the nearly universal cNFs (including the various forms of the most common, discreet cNFs or the rarer diffusely infiltrating dermal neurofibromas [Ortonne et al., 2018Ortonne N. Wolkenstein P. Blakeley J.O. Korf B. Plotkin S.R. Riccardi V.M. et al.Cutaneous neurofibromas: current clinical and pathologic issues.Neurology. 2018; 91: S5-S13Crossref PubMed Scopus (52) Google Scholar]) to the uncommon but potentially fatal sarcomas and gliomas in people with NF1. The contribution of altered regulation of RAS to cNF formation, growth, and maintenance is explored in detail in the article “RAS signaling gone awry in skin: the complex role of RAS in cutaneous neurofibroma pathogenesis, emerging biological insights” (Rhodes et al., 2023Rhodes S.D. McCormick F. Cagan R.L. Bakker A. Staedtke V. Ly I. et al.RAS signaling gone awry in skin: the complex role of RAS in cutaneous neurofibroma pathogenesis, emerging biological insights.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Scopus (0) Google Scholar). Although the specific RAS isoforms activated in cNF development have yet to be defined, RAS and its down and upstream effectors are leading targets for cNF therapeutic development (Figure 1a). Furthermore, there are compelling developments highlighting the relatively protective role of germline loss of NF1 against malignancy versus the causative role of somatic NF1 alterations in common cancers, including melanoma (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar). These observations indicate that there may be a complex balance in RAS regulation between benign and malignant tumors that, once understood, can be therapeutically harnessed (Figure 1a). Key challenges in the treatment or prevention of cNFs are their multiplicity and variability in clinical and molecular features across people with NF1 and even across tumors in a single individual. There are many factors that contribute to the regulation of cNF multiplicity addressed in the article “Cutaneous Neurofibroma Heterogenetity: Factors that Influence Tumor Burden in Neurofibromatosis Type 1” (Jiang et al., 2023Jiang C. Mckay R. Lee S. Romo C. Blakeley J. Haniffa M. et al.Cutaneous neurofibroma heterogeneity: factors that influence tumor burden in neurofibromatosis type 1.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Google Scholar). First, biallelic inactivation of the NF1 gene in Schwann cells is critical for cNF formation (and indeed, the formation of all peripheral nerve tumors in people with NF1) (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar; Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar; Staser et al., 2012Staser K. Yang F.C. Clapp D.W. Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression.Annu Rev Pathol. 2012; 7: 469-495Crossref PubMed Scopus (69) Google Scholar). The cell of origin of cNFs is defined as a boundary cap cell (Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar) or a skin-derived precursor cell (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar) derived from the embryonic dorsal nerve root and the dorsal root ganglion (DRG) (Figure 1b). These recent discoveries link NF1 loss and RAS regulation with neural and skin development and homeostasis; both helping to identify new targets and experimental endpoints for cNFs and highlighting the important interaction between skin and the peripheral nervous system (Figure 1b). Work is ongoing to define the spatial and temporal loss of somatic NF1 and how NF1 variants influence cNF behavior in skin and pNF in deep nerves. Another hallmark of cNFs is the infiltration of inflammatory cells. Recent efforts revealed that cNF development in murine models is a multistep process, involving a number of intersecting cellular and inflammatory processes (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar). Mast cells play a key role in the development of pNFs (infiltrating tumors of the peripheral nerve) where they are recruited by the chemoattractant stem cell factor secreted by NF1 null Schwann cells (Liao et al., 2018Liao C.P. Booker R.C. Brosseau J.P. Chen Z. Mo J. Tchegnon E. et al.Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis.J Clin Invest. 2018; 128: 2848-2861Crossref PubMed Scopus (78) Google Scholar; Staser et al., 2012Staser K. Yang F.C. Clapp D.W. Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression.Annu Rev Pathol. 2012; 7: 469-495Crossref PubMed Scopus (69) Google Scholar). Early studies indicate that there is also increased mast cell density in cNFs versus in uninvolved skin (with relatively higher density in small cNFs, cNFs removed from people in early adulthood, and symptomatic cNFs), but their role in tumorigenesis is still unclear (Kallionpää et al., 2022Kallionpää R.A. Ahramo K. Martikkala E. Fazeli E. Haapaniemi P. Rokka A. et al.Mast cells in human cutaneous neurofibromas: density, subtypes, and association with clinical features in neurofibromatosis 1.Dermatology. 2022; 238: 329-339Crossref PubMed Scopus (0) Google Scholar). Macrophages are also abundant in cNFs compared to unaffected skin, and there is a proposed relationship between the recruitment and proliferation of macrophages in human cNFs and the expression of YAP and TAZ, core effectors in the Hippo pathway (Jia et al., 2020Jia J. Zhang H. He L. Zhang H. Shu M. Cutaneous neurofibroma cells with active YAP promotes proliferation of macrophages resulting in increased accumulation of macrophages by modulating CCL5 and TGF-β1.Oncol Rep. 2020; 43: 1319-1330Google Scholar). Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar showed that the HOXB7 lineage−derived cells were the source cells for both cNFs and pNFs in a Hoxb7-Cre;Nf1f/fl genetically engineered mouse model and that the Hippo pathway is a key modulator of both the (more common) discrete and (rarer) diffuse cNFs. They also showed that Hippo and MAPK pathway dysregulation interact in the setting of Nf1 loss to support both cNF and pNF development (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar). Finally, in 36 cNF samples from 10 patients, genetic variation was observed in genes within the Hippo pathway (Faden et al., 2017Faden D.L. Asthana S. Tihan T. DeRisi J. Kliot M. Whole exome sequencing of growing and non-growing cutaneous neurofibromas from a single patient with neurofibromatosis type 1.PLoS One. 2017; 12e0170348Google Scholar; Gosline et al., 2017Gosline S.J. Weinberg H. Knight P. Yu T. Guo X. Prasad N. et al.A high-throughput molecular data resource for cutaneous neurofibromas.Sci Data. 2017; 4170045Crossref Scopus (13) Google Scholar). The specific relationship between NF1, Ras, cNF formation, and alterations in the Hippo pathway is yet to be elucidated. This is of particular interest for cNFs because there are several therapeutics (systemic and topical) that are effective for regulation of altered Jak–signal transducer and activator of transcription (STAT) signaling in skin conditions such as atopic dermatitis and psoriasis (Chovatiya and Paller, 2021Chovatiya R. Paller A.S. JAK inhibitors in the treatment of atopic dermatitis.J Allergy Clin Immunol. 2021; 148: 927-940Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Papp et al., 2021Papp K. Szepietowski J.C. Kircik L. Toth D. Eichenfield L.F. Leung D.Y.M. et al.Efficacy and safety of Ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies.J Am Acad Dermatol. 2021; 85: 863-872Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The Jak−STAT pathway interacts with the Hippo pathway and may be a promising area of investigation for cNFs (Guo et al., 2021Guo P. Wang Z. Zhou Z. Tai Y. Zhang A. Wei W. et al.Immuno-hippo: research progress of the hippo pathway in autoimmune disease.Immunol Lett. 2021; 230: 11-20Crossref Scopus (4) Google Scholar; Rosmarin et al., 2020Rosmarin D. Pandya A.G. Lebwohl M. Grimes P. Hamzavi I. Gottlieb A.B. et al.Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial.Lancet. 2020; 396: 110-120Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar; Wang et al., 2018Wang E.H.C. Sallee B.N. Tejeda C.I. Christiano A.M. JAK inhibitors for treatment of alopecia areata.J Invest Dermatol. 2018; 138: 1911-1916Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Finally, there are emerging data about the relationship between neuronal tissue and other cell components in cNFs such as Schwann cells and the cells of the microenvironment. This includes potential contributions of neurturin and artemin signaling between aberrant C-fiber terminals and Schwann cells in the dermis contributing to both the initiation and propagation of early-stage cNFs (Rice et al., 2019Rice F.L. Houk G. Wymer J.P. Gosline S.J.C. Guinney J. Wu J. et al.The evolution and multi-molecular properties of NF1 cutaneous neurofibromas originating from C-fiber sensory endings and terminal Schwann cells at normal sites of sensory terminations in the skin.PLoS One. 2019; 14e0216527Crossref Scopus (10) Google Scholar). This finding is reminiscent of the critical role of cells derived from the DRG in cNF development in preclinical models of cNF (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar) (Figure 1b). As addressed by Jiang et al., 2023Jiang C. Mckay R. Lee S. Romo C. Blakeley J. Haniffa M. et al.Cutaneous neurofibroma heterogeneity: factors that influence tumor burden in neurofibromatosis type 1.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Google Scholar, an improved understanding of the factors that contribute to cNF heterogeneity (cell specific, tissue intrinsic, and systemic) will enable therapeutic development for both prevention and treatment of cNFs. An important element in a functional pipeline for therapeutic discovery and development for cNFs is the availability of feasible and informative model systems relative to human disease. Fortunately, tremendous progress has been made in the development and validation of preclinical models and their use for therapeutic assessment. These models range from two-dimensional semi-immortalized cell cultures to three-dimensional cocultures, human induced pluripotent stem cells harboring NF1 gene sequence variations, and multiple in vivo models (fly, mouse, pig) (Figure 1c) (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; King et al., 2020King L.B. Boto T. Botero V. Aviles A.M. Jomsky B.M. Joseph C. et al.Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila.PLoS Genet. 2020; 16e1008920Crossref Scopus (7) Google Scholar; Li et al., 2016Li H. Chang L.J. Neubauer D.R. Muir D.F. Wallace M.R. Immortalization of human normal and NF1 neurofibroma Schwann cells.Lab Invest. 2016; 96: 1105-1115Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar; Mazuelas et al., 2020Mazuelas H. Carrió M. Serra E. Modeling tumors of the peripheral nervous system associated with Neurofibromatosis type 1: reprogramming plexiform neurofibroma cells.Stem Cell Res. 2020; 49102068Crossref Scopus (6) Google Scholar; Mo et al., 2021Mo J. Anastasaki C. Chen Z. Shipman T. Papke J. Yin K. et al.Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins.J Clin Invest. 2021; 131e139807Crossref Scopus (24) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar; Stemmer-Rachamimov et al., 2004Stemmer-Rachamimov A.O. Louis D.N. Nielsen G.P. Antonescu C.R. Borowsky A.D. Bronson R.T. et al.Comparative pathology of nerve sheath tumors in mouse models and humans.Cancer Res. 2004; 64: 3718-3724Crossref PubMed Scopus (73) Google Scholar). The applicability of each of the models to specific questions pertinent to cNF therapeutic development is addressed in the article by Staedtke et al., 2023Staedtke V. Topilko P. Le L. Grimes K. Largaespada D.A. Cagan R.L. et al.Existing and Developing Preclinical Models for Neurofibromatosis Type 1-related cutaneous Neurofibromas.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Google Scholar, “Existing and Developing Preclinical Models for Neurofibromatosis Type 1-related Cutaneous Neurofibromas.” One important role of these models is to enable the investigation of the temporal and spatial influence of Nf1 variants on the behavior of the various cells that make up cNFs. As such, these models enable therapeutic discovery for the condition NF1 (cNFs and other manifestations) as well as skin conditions influenced by the RAS−MAP kinase pathways. Despite the nearly universal presence of cNFs in people with NF1, the natural history of cNFs is not fully elucidated. It is well-documented that cNFs become apparent later in life than pNFs and increase in number and perhaps size over decades (Cannon et al., 2018Cannon A. Chen M.J. Li P. Boyd K.P. Theos A. Redden D.T. et al.Cutaneous neurofibromas in neurofibromatosis type I: A quantitative natural history study.Orphanet J Rare Dis. 2018; 13: 31Crossref PubMed Scopus (28) Google Scholar; Ehara et al., 2018Ehara Y. Yamamoto O. Kosaki K. Yoshida Y. Natural course and