Abstract: CIC::DUX4 sarcoma (CDS) is a rare, aggressive malignancy predominantly affecting children and adolescents. Characterized by CIC and DUX4 translocations, CDS accounts for less than 1% of sarcomas and is associated with rapid chemoresistance and poor clinical outcomes, with metastatic cases having a median survival of less than one year. Current treatments, adapted from small round cell sarcoma protocols, have shown limited efficacy. The rarity of CDS, coupled with the absence of robust experimental models, has significantly impeded the development of targeted therapies. To address these challenges, we developed a novel induced pluripotent stem cell (iPSC)-based model that incorporates both the genetic driver (CIC::DUX4) and the epigenetic landscape of cancer-initiating cells. This approach enables the study of permissive cell lineages with embryonic characteristics, creating a microenvironment conducive to malignant transformation. Our model provides a platform to investigate early transformation events, the cell of origin, tumor-immune interactions, stromal contributions, and tumor heterogeneity. We demonstrated that CIC::DUX4 expression in iPSC-derived differentiating cells leads to tumor formation with histological and molecular features consistent with CDS. From these tumors, we derived iCDS cell lines that retain the molecular signature of CDS in vitro and form tumors in vivo. Additionally, CIC::DUX4 was shown to suppress MHC-I presentation, facilitating immune evasion and promoting tumor growth in an immunocompetent environment. Importantly, our model provides critical insights into the cell of origin for CDS. The tools and findings from this study offer a powerful resource for the CDS research community and provide a versatile platform to study other rare malignancies, particularly those with low mutation burdens and lacking experimental models, such as other small round blue cell sarcomas.
Funding Source: Children's Cancer Research Fund, Department of Defense
