Background: Ovarian cancer is the most fatal gynecologic cancer. While curative treatments exist for early- stage cancers, there is a lack of specific biomarkers for detecting preneoplastic lesions, which usually occur in the fallopian tube epithelia (FTE). Normal FTE consists of small clusters of secretory and ciliated cells intermixed in an approximately 1:1 ratio. Although the mechanism of FTE transformation is not fully understood, it is believed that hormones and growth factors in the follicular fluid expose FTE to genotoxic stress during ovulation and that escape from the stress-induced cell death leads to an aberrant accumulation of secretory cells. In this microenvironment, secretory cells sometimes undergo genetic and morphologic changes that include stratification, atypia, and loss of cell polarity, which are considered the precursor lesions to ovarian cancer. Aberrant secretory cell accumulation is associated with an increased risk of ovarian cancer and is more common in women with germline BRCA1 mutations. However, the morphologic changes and molecular mechanisms that lead to secretory cell transformation are unknown. Specifically, the role of ciliated cells in the formation of precursor FTE lesions is unknown. Preliminary data: Our histologic and molecular analyses of FTE from BRCA1 mutation carriers and non-carriers revealed that postmenopausal BRCA1 mutation carriers have a higher ratio of secretory to ciliated cells and increased levels of the cell survival-associated genes CDK1 and Survivin, suggesting that secretory cells escape cell death. Unexpectedly, we observed that homotypic cell segregation and loss of ciliated cells precede secretory cell accumulation. Hypothesis: We propose that homotypic cell signaling and loss of ciliated cells create a favorable microenvironment for secretory cell transformation in BRCA1 mutant FTE providing that other conditions, such as hormonal changes and genotoxic stress, coincide and tip the balance toward uncontrolled proliferation. Unique resources: We are the first group to differentiate induced pluripotent stem cells (iPSCs) into FTE and establish iPSC organoids from BRCA1 mutation carriers and non-carriers. We have one of the largest collections of FTE specimens with detailed clinicopathologic and demographic data from high-risk patients. We will leverage our recently developed computational imaging convolutional neural networks pipeline for extraction of ?hidden? preneoplastic characteristics for biomarker development and identification of potential targets for prevention.
Specific Aims :
In Aim 1, we will use human and mouse FTE organoids and in vivo mouse models to test the hypothesis that ciliated cells protect secretory cells from genotoxic stress.
In Aim 2, we will test the hypothesis that aberrant secretory cell survival under genotoxic stress can be counteracted by pharmacologic inhibitors of genes involved in cell survival, such as CDK1 and Survivin.
In Aim 3, we will integrate RNA sequencing and image processing with deep-neural network learning to identify clinically-relevant molecular and histomorphometric biomarkers of preneoplastic lesions in fallopian tubes from BRCA1 mutation carriers. Impact: This research will lead to a better understanding of the interplay between predisposing genetic mutations and the microenvironmental changes that precede ovarian cancer initiation. Identifying potential molecular and morphometric contributors to the formation of the precancer niche will assist in the development of new strategies for ovarian cancer prevention and detection, which are urgently needed in clinical practice.
Women are the fastest growing subgroup of United States Veterans and policy makers are cognizant of the demand on resources for the health and well-being of women Veterans. While some cancers that affect women, such as cervical and breast cancer, have seen a dramatic reduction in mortality due to advances in prevention and early detection, the cure rate for ovarian cancer has not changed in four decades and remains below 40%. The results of this project will lead to a better understanding of the microenvironmental changes that precede ovarian cancer initiation. Such information is necessary to develop strategies for ovarian cancer prevention and early detection, which are urgently needed in clinical practice.
