Modeling endometrial cancer using iPSC-derived endometrial organoids integrating genetic determinants of ethnicity

BACKGROUND: Endometrial cancer is the most common gynecologic cancer in developed countries with an increasing incidence of 28.3 per 100,000 women per year in the United States alone. The cancer arises from the glandular epithelium of the endometrium and typically progresses by invading the stroma and myometrium. Development of endometrial cancer is influenced by genetic mutations (PTEN, TP53, mismatch repair genes), as well as ethnic, environmental, and hormonal factors. A scalable, physiologically relevant human model of endometrial cancer that captures these complex factors remains lacking. METHODS & RESULTS: We have established human induced pluripotent stem cell ( iPSC)-derived endometrial organoids as a platform for studying the early mechanisms of endometrial cancer, including cancer initiation and progression. We first used different protocols to create endometrial-like epithelium and stroma. Human iPSCs from a healthy individual were differentiated into epithelial organoids consisting of early-stage Müllerian duct-like cells (MDLCs) with an epithelial-mesenchymal hybrid phenotype (Pan-CK+/VIM+). To promote endometrial identity, epithelial organoids were co-cultured with endometrial stromal cells and treated with a single cycle of steroid hormones mimicking the human menstrual cycle. Immunofluorescence staining showed the organoids developed luminal epithelial and glandular-like structure (KRT8+/PAX8+/CDH1+), surrounded by VIM+ mesenchymal cells. Endometrial organoids are hormone responsive and express functional markers of uterine endometrium, including the secreted proteins, PRL and IGFBP1. By incorporating iPSCs from individuals of diverse ethnic backgrounds and introducing pathogenic genetic variants, we aim to uncover how genetic variation and population-specific factors contribute to endometrial cancer development and progression. CONCLUSIONS: We anticipate this model will enable us to study the multifactorial contributors to endometrial cancer and support the identification of early disease events and therapeutic targets.