Graduation Date

Fall 12-15-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Cheng Wang

Second Advisor

John S. Davis

Third Advisor

Jixin Dong

Abstract

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity is essential for granulosa cell proliferation and survival to support follicle growth. However, overactive YAP impaired differentiation and stimulated malignant transformation of granulosa cells, indicating that YAP overactivation may play a role in the development of granulosa cell tumors which come from failure of terminal differentiation of granulosa cells to luteal cells. This idea was further supported by the overexpression of YAP detected in the human granulosa cell tumor tissues and the critical role of YAP in the progression of granulosa cell tumor.

High-grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian cancer. A novel mesenchymal subtype of HGSOC has been recently identified by both The Cancer Genome Atlas and Australian Ovarian Cancer Study studies and the origin of this subtype has yet to be defined. Here, my studies show that YAP can induce high-grade ovarian cancers with mesenchymal features from poorly differentiated granulosa cells. In xenograft mouse models, overactive YAP elicits malignant ovarian cancer development in the peritoneum of host mice from poorly differentiated human granulosa cells. These tumors presented in mouse peritoneum as typical human HGSOC morphologically, histologically, and genetically. However, these tumors overexpressed N-cadherin and vimentin but had low expression of CA125 and E-cadherin, features reminiscent of the recently identified mesenchymal HGSOC. These studies suggest that granulosa cells may be a cell-of-origin for the mesenchymal type of HGSOC.

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