PNNL

Abstract

Cutaneous neurofibromas (cNFs) are benign tumors that arise from nerve terminals located in the epidermis of patients affected by Neurofibromatosis Type 1 syndrome (NF1). cNFs are fundamentally benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless they can cover a significant proportion of the body, with some patients developing hundreds to thousands of individual lesions. cNFs can cause pain, itching, and disfigurement with substantial socio-emotional repercussions. To date, surgical removal is the only treatment, but can result in scarring and the leave a potential for regrowth. To support drug discovery efforts focused on identifying effective systemic therapies for cNF, we introduce an approach to routinely establish and screen cNF tumor organoids. We optimized conditions to support ex vivo growth of genomically-diverse cNFs. Patient-derived cNF organoids closely recapitulate the molecular and cellular heterogeneity of these tumors as measured by immunohistopathology, DNA methylation, RNA-seq and flow cytometry. Our tractable patient-derived cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner. Going forward we plan to expand our approach to additional tumors to fully leverage the heterogeneity of MPNST to identify specific pathways activated in chr8 amplified tumors that can be targeted by existing drugs.