Reciprocal interactions between Beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: A different perspective in epithelial biology

Anchorage and growth factor independence are cardinal features of the transformed phenotype. Although it is logical that the two pathways must be coregulated in normal tissues to maintain homeostasis, this has not been demonstrated directly. We showed previously that down-modulation of {beta}1-integrin signaling reverted the malignant behavior of a human breast tumor cell line (T4-2) derived from phenotypically normal cells (HMT-3522) and led to growth arrest in a threedimensional (3D) basement membrane assay in which the cells formed tissue-like acini (14). Here, we show that there is a bidirectional cross-modulation of {beta}1-integrin and epidermal growth factor receptor (EGFR) signaling via the mitogenactivated protein kinase (MAPK) pathway. The reciprocal modulation does not occur in monolayer (2D) cultures. Antibodymediated inhibition of either of these receptors in the tumor cells, or inhibition of MAPK kinase, induced a concomitant downregulation of both receptors, followed by growth-arrest and restoration of normal breast tissue morphogenesis. Crossmodulation and tissue morphogenesis were associated with attenuation of EGF-induced transient MAPK activation. To specifically test EGFR and {beta}1-integrin interdependency, EGFR was overexpressed in nonmalignant cells, leading to disruption of morphogenesis and a compensatory up-regulation of {beta}1-integrin expression, again only in 3D. Our results indicate that when breast cells are spatially organized as a result of contact with basement membrane, the signaling pathways become coupled and bidirectional. They further explain why breast cells fail to differentiate in monolayer cultures in which these events are mostly uncoupled. Moreover, in a subset of tumor cells in which these pathways are misregulated but functional, the cells could be 'normalized' by manipulating either pathway

Survivor: A Fine-Grained Intrusion Response and Recovery Approach for Commodity Operating Systems

International audienceDespite the deployment of preventive security mechanisms to protect the assets and computing platforms of users, intrusions eventually occur. We propose a novel intrusion survivability approach to withstand ongoing intrusions. Our approach relies on an orchestration of fine-grained recovery and per-service responses (e.g., privileges removal). Such an approach may put the system into a degraded mode. This degraded mode prevents attackers to reinfect the system or to achieve their goals if they managed to reinfect it. It maintains the availability of core functions while waiting forpatches to be deployed. We devised a cost-sensitive response selection process to ensure that while the service is in a degraded mode, its core functions are still operating. We built a Linux-based prototype and evaluated the effectiveness of our approach against different types of intrusions. The results show that our solution removes the effects of the intrusions, that it can select appropriate responses, and that it allows services to survive when reinfected. In terms of performance overhead, in most cases, we observed a small overhead, except in the rare case of services that write many small files asynchronously in a burst, where we observed a higher but acceptable overhead