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Cell motility is a critical feature of invasive tumour cells that is governed by complex signal transduction events. Particularly, the underlying mechanisms that bridge extracellular stimuli to the molecular machinery driving motility remain partially understood. Here, we show that the scaffold protein CNK2 promotes cancer cell migration by coupling the pro-metastatic receptor tyrosine kinase AXL to downstream activation of ARF6 GTPase. Mechanistically, AXL signalling induces PI3K-dependent recruitment of CNK2 to the plasma membrane. In turn, CNK2 stimulates ARF6 by associating with cytohesin ARF GEFs and with a novel adaptor protein called SAMD12. ARF6-GTP then controls motile forces by coordinating the respective activation and inhibition of RAC1 and RHOA GTPases. Significantly, genetic ablation of CNK2 or SAMD12 reduces metastasis in a mouse xenograft model. Together, this work identifies CNK2 and its partner SAMD12 as key components of a novel pro-motility pathway in cancer cells, which could be targeted in metastasis. Cancer cell motility is necessary for cell invasion and metastasis. Here, the authors identify CNK2 as a key mediator of cancer cell motility, linking extracellular stimuli via AXL signalling and downstream activation of ARF6 GTPase, resulting in increased metastasis in preclinical models. [ABSTRACT FROM AUTHOR]

A Numb- and Neutralized-independent mechanism that acts as redundantly in cell-fate specification is described showing that trafficking of the Notch ligand Delta is different in the two daughter cells. The results suggest that cells can regulate signaling pathways and influence their development fate by inhibiting the formation of individual endocytic compartments.

Guided cell migration is a key mechanism for cell positioning in morphogenesis. The current model suggests that the spatially controlled activation of receptor tyrosine kinases (RTKs) by guidance cues limits Rac activity at the leading edge, which is crucial for establishing and maintaining polarized cell protrusions at the front. However, little is known about the mechanisms by which RTKs control the local activation of Rac. Here, using a multidisciplinary approach, we identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event, that of the Drosophila border cells (BCs). We show that elimination of the vav gene impairs BC migration. Live imaging analysis reveals that vav is required for the stabilization and maintenance of protrusions at the front of the BC cluster. In addition, activation of the PDGF/VEGF-related receptor (PVR) by its ligand the PDGF/PVF1 factor brings about activation of Vav protein by direct interaction with the intracellular domain of PVR. Finally, FRET analyses demonstrate that Vav is required in BCs for the asymmetric distribution of Rac activity at the front. Our results unravel an important role for the Vav proteins as signal transducers that couple signalling downstream of RTKs with local Rac activation during morphogenetic movements. [ABSTRACT FROM AUTHOR]

INTRODUCTION:In France, medical devices (MDs) for home-based infusion used to be covered by the health insurance system if included on the list of products and services qualifying for reimbursement under a generic description corresponding to a class of products with the same indications. This coverage modality offered no resistance to unnecessary or wasteful spending. Besides, between 2010 and 2015 the expenditure related to these MDs have increased from EUR192million to EUR289million (+50 percent).METHODS:The French National Authority for Health (HAS) has assessed the actual benefit of these MDs which have the same indications as the drugs infused at home. This work led to standardize the infusion types (gravity, elastomeric pump or active system requiring an energy source) and the quantities of MDs needed to carry out the different cares (installation, connection, withdrawal) according to the infusion route. At this step, considering that the priority was to redefine the MDs required at home for each care type, no economical assessment had been conducted.RESULTS:Based on this medical assessment, the Ministry of Health has distinguished three types of infusion and three types of services (home installation, monitoring and consumables) since 2016. In total, twenty-four packages have been set up for reimbursement with non-cumulative rules. Doctors are in charge to prescribe the appropriate packages; providers and nurses determine together the optimal devices needed for each patient according to his environment.CONCLUSIONS:These HAS recommendations on practice standardization have been the keystone for cost negotiations. The new coverage modalities aim to motivate liberal nurses to choose the best fitted products and providers to deliver the right quantities to patients. The expected benefits are an adjusted evaluation of the necessary equipment and a control of health expenditure due to the fixed costs of each infusion package. [ABSTRACT FROM AUTHOR]

INTRODUCTION:Post-approval studies (PAS) constitute an important tool in medical devices (MD) assessment usually supported by registries. However, registries are often poorly designed or incomplete. The French health insurance databases are organized since 2003 into a digital data warehouse, the Système national d'information inter-régime de l'assurance maladie (SNIIR-AM), and is the main source of information on patients, hospital activity and associated expenditure. The aim of the study was to determine if these medico-administrative data can be sufficiently relevant to guide a renewal of MD reimbursement in the context of registry failure.METHODS:The initial PAS aimed to assess the impact of the guidelines on practice (characteristics of patients, type of stenosis, indications, use of cerebral protection system, surgical procedure) and to determine the 30-day cumulative morbidity and mortality rate of endovascular procedure associated with stenting. Medico-administrative databases provide information on age, sex, symptomatic or asymptomatic stenosis in-hospital mortality and long-term mortality (with a linkage to epidemiological data) and morbidity estimated by ischemic stroke.RESULTS:The database allowed selection of a cohort of 2,071 patients in whom carotid stenting was performed in 161 centers (40 percent of stents were implanted in 14 centers) with a follow-up of 1 year. Carotid stents were mainly implanted in asymptomatic patients (81.6 percent). Morbi-mortality in symptomatic patients at 30 days (9.2 percent: 5.7 percent stroke and 3.4 percent mortality) was similar with results observed in a French comparative study EVA-3S (9.6 percent: 2.8 percent stroke and 8.8 percent mortality). These data allow the concerned HAS (French Health Authority) committee to renew the reimbursement proposal of these stents.CONCLUSIONS:Medico-administrative database collecting robust criteria can be used to support reimbursement renewal of high risk implantable medical devices. The implementation of other criteria including the disease etiology and the complications imputability may allow to consider the use of these data for non-invasive MD. [ABSTRACT FROM PUBLISHER]