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A High-Fidelity and Ancestrally Inclusive Patient-Derived Organoid Platform Resolves Cancer Cell Plasticity in
Santhilal Subhash1,2,3, Marie-Thérèse Bammert1,3, Brian Yueh1,3
1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724, USA.
Biorxiv : the Preprint Server for Biology
|July 10, 2026
Summary
Researchers developed patient-derived organoids from uterine carcinosarcoma (UCS), a rare endometrial cancer. These models capture tumor biology and patient diversity, offering new avenues for studying cancer cell plasticity and identifying therapeutic vulnerabilities.
Area of Science:
- Oncology
- Cancer Biology
- Genomics
Background:
- Uterine carcinosarcoma (UCS) is a rare, aggressive endometrial cancer with poor prognosis.
- UCS is characterized by biphasic histology (epithelial and mesenchymal cells) and early metastasis.
- Existing patient-derived models are scarce and lack ancestral diversity, hindering research, particularly for underrepresented populations.
Purpose of the Study:
- To establish and characterize faithful, ancestrally inclusive patient-derived organoids (PDOs) for uterine carcinosarcoma (UCS).
- To utilize these PDOs to study cancer cell plasticity and identify potential therapeutic vulnerabilities in UCS.
- To address the inequity in UCS research by including diverse patient populations.
Main Methods:
- Established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort and matched normal endometrial tissues.
- Characterized PDOs using histology, multi-platform sequencing (genomics, transcriptomics), and single-cell analysis.
- Performed proof-of-concept therapeutic testing targeting identified vulnerabilities.
Main Results:
- UCS PDOs accurately recapitulated biphasic histology, genomic landscape, and cancer cell plasticity of original tumors.
- Models remained stable across passages and expanded for extended periods (up to 28 months).
- Therapeutic testing identified CREB inhibition and combined FGFR/YAP inhibition as potential vulnerabilities.
Conclusions:
- Developed a histologically, genomically, and transcriptionally faithful UCS organoid platform.
- The platform is ancestrally inclusive and captures patient-specific cancer cell plasticity.
- This resource enables the study of UCS vulnerabilities and promotes equitable research in an aggressive cancer.
