Establishment of a patient-derived malignant peripheral nerve sheath tumor organoid model reveals SHH pathway activation and therapeutic vulnerability.

Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma of presumed peripheral nerve sheath origin, for which effective systemic therapies remain limited. The biological mechanisms underlying its progression and therapeutic vulnerabilities are not fully understood, partly due to the lack of reliable patient-derived models. In this study, we attempted to establish organoid cultures from two clinically and pathologically unusual cases of MPNST using a modified air-liquid interface method. A stable organoid line was successfully generated from one case, and a corresponding organoid-derived xenograft (ODX) model was established. Both the organoid and ODX retained the histological, immunophenotypic, and genomic features of the original tumor. Comparative molecular analyses revealed shared copy number alterations involving NF1 and SUZ12 in both cases, suggesting underlying biological similarity. In the organoid-forming case, whole-exome and transcriptomic analyses identified a loss-of-function alteration in PTCH1 and activation of the Sonic Hedgehog (SHH) signaling pathway. Consistent with these findings, treatment with the Smoothened inhibitor vismodegib significantly suppressed organoid growth and downregulated SHH-related gene expression. These results indicate that SHH pathway activation may represent a therapeutically actionable vulnerability in a subset of MPNST. Our study establishes a patient-derived organoid model of MPNST and highlights its utility as a preclinical platform for investigating tumor biology and evaluating targeted therapies in this rare malignancy.