Cutaneous neurofibromas (CNFs) are benign tumors that occur in the dermis of individuals with the inherited tumor predisposition disorder, neurofibromatosis type 1. CNFs cause disfigurement, pain, burning, and itching, resulting in substantially reduced QOL in patients with neurofibromatosis type 1. 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 patients with neurofibromatosis type 1. 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. Furthermore, 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 the expression of proinflammatory genes, confirming that CNF PDEs are a useful model for both mechanistic studies and preclinical drug testing.

中文翻译：

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神经纤维瘤病 1 型相关皮肤神经纤维瘤的体外患者衍生外植体模型


皮肤神经纤维瘤 (CNF) 是一种良性肿瘤，发生在患有遗传性肿瘤易感性疾病（1 型神经纤维瘤病）的个体的真皮中。CNF 会导致毁容、疼痛、烧灼感和瘙痒，导致 1 型神经纤维瘤病患者的生活质量大幅下降。是表现出细胞和分子异质性的良性肿瘤，因此很难开发易于处理的体外或体内模型。因此，CNF 研究和药物发现工作受到限制。为了满足这一需求，我们使用 1 型神经纤维瘤病患者的 CNF 肿瘤开发了一种可重复的患者来源的外植体 (PDE) 离体培养模型。CNF PDE 在培养物中保持活力超过 9 天，并概括了 CNF 的细胞组成和分子信号传导。使用 CNF PDE 作为模型系统，我们发现增殖与 T 细胞浸润增加相关。此外，我们还发现了 CNF PDE 中的一种相互炎症信号传导模式，其中肿瘤依赖于前列腺素或白三烯介导的信号传导途径。作为原理证明，我们证明离体糖皮质激素治疗减少了促炎基因的表达，证实 CNF PDE 是机制研究和临床前药物测试的有用模型。