The human endometrium (inner lining of the uterus) undergoes hormone-regulated cycles of growth and shedding. Aberrations in this process are known to contribute to many diseases, such as infertility, endometriosis, and cancer. Due to obesity and other lifestyle factors, there is a significant rise in the number of cases of endometrial diseases. Therefore, there is an urgent need to develop preclinical models mimicking normal and disease human endometrium to develop new targeted approaches for patients with endometrial diseases.
Recently, the three-dimensional culture of endometrial epithelial cells has been developed to generate organoids which resemble their organ of origin. We developed organoids from normal (n=3) and endometrial cancer tissues (n=7) collected from patients undergoing hysterectomies at the John Hunter Hospital. These organoids expressed makers of the human endometrial epithelium (Cytokeratin 8), glands (Foxa2), and ciliated cells (HFH4), confirming these organoids mimic human endometrium.
Abnormal canonical Wnt signaling is involved in the pathogenesis of endometriosis, adenomyosis, and endometrial cancer. Our previous work has established that overactivation of this pathway leads to the development of endometrial hyperplasia and cancer in mouse models (Goad et al Carcinogenesis 2019). In this study, we investigated if targeting Wnt/b-catenin signaling in human endometrial cancer is a viable strategy to reduce the growth of cancer cells. We cultured human endometrial organoids in the presence of two well-known Wnt inhibitors (IWR1 and IWP2) and found a significant reduction in colony formation efficiency (0.36-fold in normal and 0.55-fold in cancer) and cell proliferation (0.45-fold in normal and 0.37-fold in cancer). We showed that these two inhibitors specifically targeted canonical Wnt signaling by examining the expression of active b-catenin protein. We are now developing organoids from additional patents covering several different histotypes of endometrial cancer to understand which group patients are more likely to respond to therapies targeting Wnt/ b-catenin signaling.