The most common and most lethal type of ovarian cancer is high grade serous carcinoma (HGSC). Over the last 15 years it has become increasingly apparent that the majority of “ovarian” HGSCs actually originate from the fallopian tube epithelium with secondary involvement of the ovaries. This breakthrough in the understanding of ovarian HGSC pathogenesis was discovered by pathologists who carefully examined fallopian tubes under the microscope and recognized early carcinomas and histologically atypical lesions in the fallopian tube fimbria. These early carcinomas are identified in ~5% of fallopian tubes and ovaries removed from women at high risk for developing ovarian cancer, and also in women with advanced HGSC. This discovery was critical as we now understand that removing the fallopian tubes from women at risk for developing ovarian cancer can prevent the HGSC from occurring or remove cancerous lesions before they spread to other organs. Even earlier lesions in the fallopian tube have also been identified under the microscope (“p53 signatures”), which can share genetic mutations with early and advanced carcinomas, but are also fairly common in healthy women, suggesting that these p53 signatures in isolation do not increase risk of developing HGSC. Interestingly, little is known about the cellular makeup of the normal fallopian tube. Our current knowledge of the epithelial cell types present in the human fallopian tube is crude, with 3 different cell types recognized histologically. Thus, there is a significant gap in knowledge with regard to the specific cell(s) of origin for HGSC. Defining the epithelial cells present in the fallopian tube and other putative cells of origin is critical to our understanding of HGSC pathogenesis. In other organ systems it has become clear that non-neoplastic epithelial cell populations are far more complex than can be appreciated with histology, special stains, and traditional molecular analyses.
This project is designed to address the hypothesis that it is ultimately multiple epithelial cell types in the fallopian tube, that differ fundamentally in both pathophysiology and spatial distribution, that contribute to variation in tumorigenesis, tumor biology, and clinical behavior in HGSC. My goal is to create an atlas of cell Types present in the human fallopian tube by performing detailed molecular analyses of tens of thousands of individual cells. Determining the cell(s) of origin for HGSC will have serious implications for disease prevention and will lead to insights regarding novel targeted therapy in HGSC.