The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility

Deubiquitinating enzymes are now emerging as potential therapeutic targets that control many cellular processes, but few have been demonstrated to control cell motility. Here, we show that ubiquitin-specific protease 17 (USP17) is rapidly and transiently induced in response to chemokines SDF-1/CXCL12 and IL-8/CXCL8 in both primary cells and cell lines, and that its depletion completely blocks chemokine-induced cell migration and cytoskeletal rearrangements. Using live cell imaging, we demonstrate that USP17 is required for both elongated and amoeboid motility, in addition to chemotaxis. USP17 has previously been reported to disrupt Ras localization and we now find that USP17 depletion blocks chemokine-induced subcellular relocalization of GTPases Cdc42, Rac and RhoA, which are GTPases essential for cell motility. Collectively, these results demonstrate that USP17 has a critical role in cell migration and may be a useful drug target for both inflammatory and metastatic disease

Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms

Adhesion and migration are integrated cell functions that build, maintain and remodel the multicellular organism. In migrating cells, integrins are the main transmembrane receptors that provide dynamic interactions between extracellular ligands and actin cytoskeleton and signalling machineries. In parallel to integrins, other adhesion systems mediate adhesion and cytoskeletal coupling to the extracellular matrix (ECM). These include multifunctional cell surface receptors (syndecans and CD44) and discoidin domain receptors, which together coordinate ligand binding with direct or indirect cytoskeletal coupling and intracellular signalling. We review the way that the different adhesion systems for ECM components impact cell migration in two- and three-dimensional migration models. We further discuss the hierarchy of these concurrent adhesion systems, their specific tasks in cell migration and their contribution to migration in three-dimensional multi-ligand tissue environments

Mesenchymal Cell Interaction with Ovarian Cancer Cells Triggers Pro-Metastatic Properties

Tumor microenvironement is an important actor of ovarian cancer progression but the relations between mesenchymal cells and ovarian cancer cells remain unclear. The objective of this study was to determine the ovarian cancer cells' biological modifications induced by mesenchymal cells. To address this issue, we used two different ovarian cancer cell lines (NIH:OVCAR3 and SKOV3) and co-cultured them with mesenchymal cells. Upon co-culture the different cell populations were sorted to study their transcriptome and biological properties. Transcriptomic analysis revealed three biological-function gene clusters were enriched upon contact with mesenchymal cells. These were related to the increase of metastatic abilities (adhesion, migration and invasion), proliferation and chemoresistance in vitro. Therefore, contact with the mesenchymal cell niche could increase metastatic initiation and expansion through modification of cancer cells. Taken together these findings suggest that pathways involved in hetero-cellular interaction may be targeted to disrupt the acquired pro-metastatic profile