Chondrosarcoma organoids reveal SHH pathway activation driven by PTCH1 and BCOR alterations

Abstract

Abstract Chondrosarcoma is the second most common malignant bone tumor, characterized by the production of cartilaginous matrix and a high degree of resistance to conventional therapies such as chemotherapy and radiotherapy. Effective treatment options remain limited, highlighting the urgent need for preclinical models to explore novel therapeutic approaches. This study aimed to establish patient-derived organoid (PDO) models of chondrosarcoma and to investigate their utility in elucidating molecular mechanisms and drug responses. Chondrosarcoma specimens were collected from patients and cultured using a modified air–liquid interface (ALI) organoid method. The resulting PDO were serially expanded in vitro and transplanted into NOD-SCID IL2Rgnull mice for in vivo validation. Histological and genetic analyses were performed to compare organoids with the corresponding primary tumors. Whole-exome profiling was used to identify genetic alterations. Organoid-based drug sensitivity testing was conducted using vismodegib, a Sonic Hedgehog (SHH) pathway inhibitor. Two PDO lines were successfully established. Organoid-derived xenografts preserved the histological and genetic features of the parental tumors. Genomic profiling revealed loss-of-function mutations in PTCH1 and BCOR , suggesting activation of the Sonic Hedgehog signaling pathway. Consistently, vismodegib exhibited strong in vitro antitumor activity, indicating functional pathway dependence. We established the first PDO models of chondrosarcoma that faithfully recapitulate key tumor features. These models provide a valuable preclinical platform for dissecting molecular pathogenesis and for advancing the development of targeted therapeutic strategies in this intractable malignancy.