Establishment and characterization of multiple patient-derived organoids from a case of advanced endometrial cancer

Area of Science:

• Oncology
• Genetics
• Drug Discovery

Background:

• Patient-derived organoids (PDOs) are valuable preclinical models that mimic patient tumors.
• Previous studies often used single PDOs, potentially overlooking intra-tumor heterogeneity.

Purpose of the Study:

• To investigate if multiple PDOs from different tumor sites can capture spatial diversity in uterine carcinosarcoma (UCS).
• To analyze genetic heterogeneity and drug sensitivity across PDOs from a single UCS patient.

Main Methods:

• Established and characterized three PDOs from distinct sites (tumor tissue, peritoneal fluid, uterine brushing) of an advanced UCS patient.
• Performed whole-exome sequencing and drug sensitivity assays on PDOs and the primary tumor.
• Conducted drug screening to identify broadly effective agents.

Main Results:

• All PDOs shared key mutations (TP53, STK11) and CCNE1 amplification but exhibited mutually exclusive KRAS or ERBB2 amplifications.
• Differential HER2 expression and sensitivity to HER2 inhibitors were observed across PDOs.
• Inter-PDO heterogeneity in response to cytotoxic agents was evident.
• Four candidate drugs showed efficacy across all tested PDOs.

Conclusions:

• Multiple PDOs effectively model the spatial genetic and phenotypic diversity of UCS.
• This multi-PDO approach enhances the reliability of PDOs for preclinical research and personalized medicine in UCS.