Uterine cancer is the 4th most frequent malignancy and the 6th cause of cancer-related deaths in women in the US. While the incidence and mortality rates of some cancers, such as lung and colorectal cancers, are declining, they are both increasing for cancers of the uterine corpus. Recent extensive integrated genomic analyses of endometrial carcinomas have provided important insights into the repertoire of molecular aberrations characteristic of these malignancies. They have also identified four major molecular subtypes of endometrial carcinoma, characterized by distinct genetic alterations and clinical behavior. However, utilization of this information is compromised because the cell(s) of origin have not been determined. By analogy with stem cells in other organs and tissues, aberrations in mechanisms governing endometrial epithelial stem cells may lead to a number of pathological conditions, including cancer. Unfortunately, the identity and location of endometrial stem cells remains insufficiently elucidated.

A number of recent studies have suggested location of stem cells either in the glandular or luminal compartments of the mouse endometrial epithelium. In humans, such cells are commonly thought to be located in the basalis segment of the endometrial glands. However, according to a recent single cell transcriptome study of secretory phase human endometrium, cells showing characteristics of stem/progenitor cells are located in the upper region of the functionalis. Other studies have suggested that endometrial epithelium can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin.

Our studies performed in mice conditionally expressing fluorescent reporters in PAX8+ cells support the hypothesis that stem cells involved in the homeostasis of endometrial epithelium are located in the epithelium proper. By using single cell transcriptome analysis, we have identified TROP2 (encoded by Tacstd2) and FOXA2 as reliable markers of luminal and glandular compartments, respectively. Our lineage trajectory predictions, organoid formation and lineage tracing experiments suggest that both luminal and glandular epithelium contain stem/progenitor cells. TROP2 and FOXA2 are also differentially expressed in human endometrial epithelium. Based on previous findings and our preliminary results we hypothesize that endometrial epithelium contains two pools of resident stem/progenitor cells, which may have different propensities for malignant transformation, thereby leading to clinically distinct neoplasms. To test this hypothesis, we will establish cell lineage hierarchy of the mouse endometrial epithelium, test susceptibility of the mouse glandular and luminal epithelium to malignant transformation associated with alterations common for serous and endometrioid carcinomas, and establish the relevance of mouse model findings to human biology.