Abstract B56: PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation

Abstract

Abstract Introduction: Many ovarian cancers likely originate in the fallopian tube and then colonize the ovary. An FTE origin for some HGSC is well established and there is increasing evidence that some endometrioid cancers may also originate in the FT. The loss of PTEN was found in 33% of STIC lesions. According to the TCGA, the PI3K/AKT pathway is altered in 45% of HGSC, and this could amplify downstream signaling similarly to the loss of PTEN, such as pAKT activation. PTEN mutations have also been found in about 20% of endometrioid ovarian carcinoma. Purpose of the Study: The signaling events involved in the onset of ovarian cancer from the fallopian tube epithelium (FTE) are crucial for early detection and treatment of the disease, but they remain poorly defined. Therefore, we aim to identify drivers of transformation and tumorigenesis from FTE. Experimental Procedures: We employed cells engineered with PTEN knocked down using shRNA and performed RNA-seq to identify the pathways involved in tumorigenesis. To uncover the mechanism underlying the invasion of cancerous fallopian tube cells to the ovary, PTEN-deficient cells were tagged with green fluorescent protein to study colonization of the ovary ex vivo. Finally, we generated a novel transgenic model of PAX8-driven loss of PTEN in the FTE to study early lesions in FT and ovarian cancer progression. Results: Conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase was sufficient to drive endometrioid and serous borderline ovarian carcinoma, providing the first model of FTE-derived borderline tumors. In addition, heterozygous PTEN deletion in the FTE resulted in hyperplasia, providing a model to study early events of ovarian cancer pathogenesis. Loss of PTEN increased cell migration, invasion, and upregulated WNT4, a key regulator of Müllerian duct development during embryogenesis. An inhibitor of the WNT canonical and noncanonical pathways, LKG-974, as well as knockdown of WNT4 by siRNA, inhibited loss of PTEN-induced migration, whereas inhibitors of the canonical pathway alone (PRI724) did not. Further investigation revealed that WNT4 was required for increased migration and colonization of the ovary by PTEN-deficient oviductal cells in a β-catenin-independent manner. WNT4 was expressed in human ovarian cancer lines, especially in OVCAR8 and OVCAR4, and in several cancer histotypes, as revealed by the TMA analysis using IHC. LKG-974 also inhibited migration in the human ovarian cancer lines OVCAR4 and OVCAR8. Conclusions: Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis. Citation Format: Angela Russo, Austin Czarnecki, Matthew Dean, Wei Jian-Jun. PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation. [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 B56.