Abstract 175: Mechanical transduction mediated by Integrin-ILK dependent actin dynamics drives stem-plasticity leading experimental metastatic colonization of prostate cancer leading experimental metastatic colonization of prostate cancer
Authors: Chen Lanpeng , Coppola Stefano , Landman Nick , Groenewoud Arwin , Schmidt Thomas , Snaar-Jagalska B.Ewa 
Published: August 2018

Incurable bone metastasis is a main cause of death in prostate cancer. Metastasis is believed to be initiated by a small subpopulation of cancer cells termed tumor initiating cells (TICs) or cancer stem-like cells (CSCs). One of the key steps of the metastatic cascade is metastatic colonization of circulating tumor cells/clusters (CTCs) in a distant niche from circulation. From clinical database analysis, a significant up regulation of genes related to cell-ECM interaction was observed in prostate cancer patients derived CSCs, implying that the enhanced focal adhesion ability and its correlated cytoskeleton remodeling of CSCs plays a critical role in regulating metastatic colonization. However, due to a lack of tools to visualize the low amount of disseminated CSCs at high imaging resolution, it remains unknown how those cells behave when they interact with the stromal compartment at the inception of metastatic colonization. Hereby, we intravenously injected osteotropic prostate cancer cells with fluorescently-labeled F-actin into transparent zebrafish embryos to monitor single cell dynamics during metastatic colonization. In this model we observed a highly dynamic actin-based cytoskeletal remodeling in ALDHhi CSCs that controls extravasation and metastatic colonization. Transcriptome analysis revealed that this cytoskeleton remodeling was regulated by the focal adhesion factors: Integrinβ1 and integrin linked kinase (ILK). Genetic targeting of Integrinβ1 and ILK significantly inhibited expression of pluripotency genes, ALDH activity, metastatic colonization and outgrowth, suggesting the Integrinβ1-ILK axis as a key metastatic regulator that drives stem-like properties of CSCs during metastasis. Further in vitro and in vivo analysis showed that the Integrinβ1-ILK axis controls prostate cancer stem plasticity by generating contractile force through small GTPase-CDC42 and invadopodia regulator-N-wasp when the cells physically interact with the ECM. This mechanical transduction further activates mechanical sensor YAP/TAZ in a hippo-independent manner and promotes the expression of pluripotency genes that support metastatic initiation. Interference with this process by blocking CDC42-N-wasp signaling significantly attenuated mechanical transduction, impaired YAP/TAZ nuclear translocation and eventually inhibited metastatic initiation. Taken together, this study indicates a fundamental role of the mechanical transduction between ECMs and CSCs mediated by integrin/ILK dependent cytoskeleton remodeling at metastatic onset and outgrowth. Pharmacological targeting of this process may be a potent approach to attenuate the formation of prostate cancer metastasis on clinic.

Citation Format: Lanpeng Chen, Stefano Coppola, Nick Landman, Arwin Groenewoud, Thomas Schmidt, B.Ewa Snaar-Jagalska. Mechanical transduction mediated by Integrin-ILK dependent actin dynamics drives stem-plasticity leading experimental metastatic colonization of prostate cancer leading experimental metastatic colonization of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 175.