Abstract B63: The role of endometrium in endometriosis-associated ovarian cancer
Authors: Wilson Michael R. , Holliday Jeanne , Su Ren-Wei , Fazleabas Asgi , Chandler Ronald L. 
Published: August 2018

Abstract
Despite being a deadly disease, debates over the origins of ovarian cancer have persisted for many decades. There is evidence that some tumors may not originate from the ovary, but are the result of cells that have moved to the ovary from elsewhere within the reproductive tract. This is supported by clinical findings showing that certain types of ovarian cancer are prevented by surgeries that modify or remove parts of the female reproductive tract, such as the fallopian tubes. Nearly a century ago, Dr. John Sampson proposed that certain types of ovarian cancer might be caused by endometriosis, a painful disease that reduces fertility and affects 5-10% of all women. Endometriosis occurs when cells lining the uterus do not flow out of the body via menstruation, but instead colonize other tissues within the reproductive tract, such as the ovaries, or in other parts of the body, including the abdomen. Although endometriosis is a risk factor for ovarian cancer, the hypothesis that cells from the uterus are capable of traveling to the ovary before giving rise to endometriosis-associated ovarian cancer (EAOC) has not been explored in model systems. Previously, our lab developed an ovarian surface epithelium-derived (OSE) genetically engineered mouse model (GEMM) of ovarian cancer with ARID1A and PIK3CA mutations. Here, we have developed a GEMM of gynecologic cancer derived from endometrial epithelium using the lactotransferrin (Ltf)-iCre allele. Using an allelic series of Ltf-iCre females carrying ARID1A mutations (flox and the V1068G point mutant) in combination with a PIK3CAH1047R activating mutation, we show that the severity of the disease correlates with ARID1A mutation status. The mutant mice develop endometrial tumors and show many features of endometriosis, including vaginal bleeding and atypical hyperplasia. Unlike our OSE GEMM, Ltf-iCre; ARID1Afl/+; PIK3CAH1047R females develop uterine tumors, suggesting that ARID1A functions as a haploinsufficient tumor suppressor. In order to facilitate extrauterine spread, unilateral uterotubal incisions were performed on the uteri of Ltf-iCre mutants in order to expose the luminal contents of the uterus to the peritoneal space. These mice developed endometrioid-like ovarian tumors and malignant ascites in an ARID1A dose-dependent manner, with females succumbing to prominent omental metastases and intraperitoneal adhesions. These results support the idea that the endometrium is a site of EAOC origin, and that endometriosis is a benign precursor of EAOC. Ongoing studies are focused on exploring molecular differences between OSE-derived and endometrium-derived tumors in order to elucidate the mechanism of ARID1A tumor-suppressor function. An understanding of the origins of EAOC will be essential to increase the clinical relevance of endometriosis, and to inform the effort towards developing early detection and preventative strategies for these cancers.
Citation Format: Michael R. Wilson, Jeanne Holliday, Ren-Wei Su, Asgi Fazleabas, Ronald L. Chandler. The role of endometrium in endometriosis-associated ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B63.