A platform for rapid patient-derived cutaneous neurofibroma organoid establishment and screening

• Published in: Cell reports methods Vol. 4; no. 5; p. 100772
• Main Authors: Nguyen, Huyen Thi Lam, Kohl, Emily, Bade, Jessica, Eng, Stefan E., Tosevska, Anela, Al Shihabi, Ahmad, Tebon, Peyton J., Hong, Jenny J., Dry, Sarah, Boutros, Paul C., Panossian, Andre, Gosline, Sara J.C., Soragni, Alice
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.05.2024; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; benign tumor; cNF tumor organoids; cutaneous neurofibroma; HTS screening; Humans; neurofibroma; Neurofibroma - pathology; Neurofibroma - surgery; Neurofibromatosis 1 - pathology; neurofibromatosis type 1; organoids; Organoids - pathology; Skin Neoplasms - pathology; HTS screening; cutaneous neurofibroma; benign tumor; cNF tumor organoids; organoids; neurofibromatosis type 1; neurofibroma; CP: Stem cell; CP: Cancer biology
• ISSN: 2667-2375; 2667-2375
• DOI: 10.1016/j.crmeth.2024.100772

Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by neurofibromatosis type 1 syndrome. cNFs are benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement resulting in substantial socio-emotional repercussions. Currently, surgery and laser desiccation are the sole treatment options but may result in scarring and potential regrowth from incomplete removal. To identify effective systemic therapies, we introduce an approach to establish and screen cNF organoids. We optimized conditions to support the ex vivo growth of genomically diverse cNFs. Patient-derived cNF organoids closely recapitulate cellular and molecular features of parental tumors as measured by immunohistopathology, methylation, RNA sequencing, and flow cytometry. Our cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner. [Display omitted] •Established patient-derived cutaneous neurofibroma (cNF) organoids from patients with NF1•CNF organoids recapitulate the molecular and cellular features of parental tumors•Identified optimal medium conditions promoting growth while maintaining cNF features•Implemented a high-throughput screening platform to find drugs slowing organoid growth There is no approved systemic or topical therapy for managing cutaneous neurofibromas (cNFs) in patients with neurofibromatosis type 1, a condition marked by the growth of tens to thousands of benign cNF tumors, which have significant quality-of-life implications. Current models largely focus on Schwann cells, yet cNFs are composed of many different cell types, including fibroblasts and macrophages. Given the genetic and cellular complexity of cNFs, we sought to develop a robust, patient-derived organoid model system that captures the heterogeneity and the molecular profile of the cNF of origin. The cNF organoids are developed in a format compatible with highthroughput screening that can facilitate drug discovery and development efforts to identify therapeutic leads. Nguyen et al. develop an approach to rapidly establish and screen cutaneous neurofibroma (cNF) organoids. These are benign tumors with no existing systemic therapy, exhibiting significant genetic and cellular heterogeneity. Patient-derived cNF organoids closely recapitulate cellular and molecular features of parental tumors and can be screened for drug discovery.