Abstract 5099: Abrogation of cancer cell extravasation in renal cell carcinoma PDX lines via invadopodia dysregulation mediated by PAK1 inhibitors

Abstract

Abstract Cellular remodeling of the extracellular matrix (ECM), facilitating tumour cell invasion, is a key intrinsic quality in metastatic cells. Invadopodia are actin-driven protease-rich subcellular membrane protrusions formed by tumor cells for localized degradation and remodeling of the ECM. Invadopodia mediate tumor cell extravasation, a key step in the metastatic cascade in which tumor cells undergo transendothelial migration when arrested at distant sites. Using several PDX cell lines, we determine that treatment with PAK1 inhibitors leads to significantly decreased rates of cancer cell extravasation in vivo (IPA-3, 1 uM final concentration) with no impacts on cell viability in vitro. Interestingly, in vitro, there was no significant change in the number of cells forming invadopodia; however, there was more gelatin degradation per cell as determined by in vitro gelatin-Alexa594 invadopodia assays. Time lapse imaging of invadopodia formation in PDX cell lines reveal a decrease in invadopodia disassembly in vitro, resulting in alterations to adhesions to maintain tumor cell anchorage to the CAM vessel wall in vivo. These results reveal the feasibility of targeting extravasation through other mechanisms whilst impairing invadopodia disassembly prior to cancer cell transportation to the underlying tissue. Citation Format: Karla Williams, Clarisse Mazzola, James Brugarolas, Nicholas Power, Ann Chambers, Hon Leong. Abrogation of cancer cell extravasation in renal cell carcinoma PDX lines via invadopodia dysregulation mediated by PAK1 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5099. doi:10.1158/1538-7445.AM2015-5099