A Patient-derived Organoid Platform for Uterine Carcinosarcoma that Emulates Disease Characteristics

Abstract Uterine carcinosarcoma (UCS) is a rare but highly lethal endometrial malignancy characterized by early dissemination, marked lineage plasticity, and limited therapeutic options. Although genomic studies have established UCS as a copy-number-high, carcinoma-like tumor with strong epithelial-mesenchymal transition (EMT) features, mechanistic and translational progress has been hindered by the lack of physiologically relevant patient-derived models, particularly models representing patients from African ancestry who are disproportionately affected by UCS. Here, we establish an ancestrally diverse cohort of UCS patient-derived organoids (PDOs) with matched normal endometrial PDOs that preserve the histological, genomic and transcriptional features of the tumors from which they were derived. Across the cohort, UCS PDOs retain somatic mutations, copy number alterations and recapitulate biphasic epithelial and mesenchymal cell states at single-cell resolution, and model dynamic transitions along an epithelial-to-mesenchymal continuum. Integrated bulk and single-cell analyses identify mesenchymal, proliferative, and metabolic transcriptional programs in UCS, with prominent enrichment of CREB-family motifs. Functionally, UCS PDOs reproduce heterogeneous responses to carboplatin and paclitaxel, reveal sensitivity to CREB inhibition, and suggest a potential cooperative vulnerability to combined FGFR and YAP pathway inhibition. Together, these data establish a genomically faithful and ancestrally inclusive UCS PDOs platform for studying tumor plasticity, lineage-state regulation, and therapy response in an understudied and clinically aggressive gynecologic cancer.