Abstract A61: Filamin A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress ovarian cancer cell invasion and metastasis

Abstract

Abstract Identifying key mediators of cancer invasion and metastasis is crucial to the development of new and more effective therapies. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important mediator of cell migration and invasion. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and ovarian cancer specimens. In addition, it was shown that intraperitoneal delivery of the FILIP1L gene resulted in inhibition of metastatic ovarian cancer spread into the peritoneum and intra-abdominal organs. Although these observations demonstrate that FILIP1L inhibits metastasis, it is not clear which step(s) of metastasis is inhibited by FILIP1L. To this end, in our present study we chose an orthotopic ovarian cancer model in mice where cancer cells metastasize to distant organs such as lungs which lung metastasis can occur through vessels, not by exfoliation and peritoneal spread. In addition, FILIP1L expression was controlled by a doxycycline-inducible expression system which enabled us to determine the direct effect of FILIP1L expression in vivo. Using this model, we observed that expression of FILIP1L in ovarian cancer cells inhibited spontaneous lung metastasis. Experimental lung metastases (established via tail vein injection of cancer cells) as well as the extravasation step of metastasis were not inhibited by FILIP1L, suggesting that FILIP1L inhibits the earlier steps of metastasis such as invasion and intravasation. FILIP1L inhibited matrix metallo¬proteinase (MMP)-dependent invasion in vivo. MMP3, -7 and -9 were transcriptionally down-regulated, and MMP9 protein expression and activity were inhibited in FILIP1L-expressing tumors. Furthermore, our studies suggest that FILIP1L regulates invasion and metastasis by inhibiting components of the WNT signaling pathway. FILIP1L expression reduced the induction of WNT target genes such as MMP3, -7 and -9, and β-catenin-directed transcriptional activity, suggesting inhibition of the canonical WNT pathway. Nuclear β-catenin, an indicator of an active canonical WNT pathway, was reduced in FILIP1L-expressing tumors. We conclude that FILIP1L reduces β-catenin levels, which leads to the transcriptional down-regulation of WNT target genes such as MMPs, resulting in inhibition of metastasis. Thus, modulation of FILIP1L expression has the potential to be a target for cancer therapy. Citation Format: Mijung Kwon, Soo Jin Lee, Yarong Wang, Yevangelina Ryvak, Alex Luna, Srilakshmi Reddy, Asha Adem, Brian Beaty, John Condeelis, Steven Libutti. Filamin A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress ovarian cancer cell invasion and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A61.