Our research focuses on the control cell polarization and migration in heath and disease and more specifically on the mechanisms regulating astrocyte migration and glioma infiltration.

Polarity is a critical parameter in most cellular functions including cell division, cell differenciation and cell division. This is reflected by the role of cell polarity during the development and also by the fact that polarity is strongly perturbed in tumors. Astrocytes are major glial cells of the central nervous system. They fulfill a wide variety of functions allowing neurons to develop, survive and function correctly. In a normal adult brain, astrocytes are essentially immobile and do not display any obvious polarized morphology. Under pathological situations involving inflammation of the cerebral tissue, astrocytes become reactive and polarize and migrate in the direction of the inflammatory site. In these conditions, polarization of the cell shape is obvious but migration is tightly regulated and rather limited. In contrast, astrocytes can give rise to very invasive tumors called gliomas. Gliomas correspond to the majority of primary brain tumors and are associated with very poor prognosis. One essential reason is the extremely high invasive capacity of gliomas and the ability of glioma cells to migrate over long distance and therefore escape to classical therapeutic treatment

Our goals is to better define the fundamental signaling pathways controlling normal astrocyte polarization and migration in inflammatory situations and to determine whether alteration of these pathways can lead to the invasive properties of gliomas.

The current questions being addressed are :

• What are the Extracellular cues controlling cell polarization and migration?

Using adhesive micropatterns and various flexible substrate, we determine how the chemical composition and the physical properties of the extracellular matrix influence cell polarity. In 2009, we have reported that cellular interactions through classical cadherins (N-cadherin, E-cadherin, VE-cadherin) control centrosome and nucleus positioning (Vallois et al. 2009) .

• How tumor suppressors contribute to the regulation of cell polarity ?

We study the regulation and the exact function of tumor suppressors which also are key polarity proteins such as Scrib, Dlg, APC and PTEN during cell migration. We have recently shown that Scrib, via the Cdc42-exchange factor βPIX, induces Cdc42 localized activation at the wound edge of astrocytes and promotes astrocyte polarization and directed migration (Osmani et al. 2006).

• How polarity pathways control the organization of the cytoskeleton during cell migration?

We investigate the role of the tumor suppressor polarity proteins mentioned above in the rearrangements, the dynamics and the membrane interactions of actin microfilaments, microtubules and intermediate filaments.

• Are alterations of polarity pathways responsible for the abnormal migration of glioma cells ? Using transcriptomic and proteomic analysis of a large library of gliomas, we investigate whether expression of polarity proteins is altered in gliomas. We also determine how changes in expression levels of these proteins affect cell polarity and migration.

ON-GOING COLLABORATIONS

• Marc Sanson and Jean-Yves Delattre, Pitié-Salpétrière, Paris.

• Mark Scott and Stephano Marullo, Institut Cochin, Paris.

• Jean-Baptiste Manneville, Institut Curie, Paris.

• Philippe Chavrier, Institut Curie, Paris.

S. Etienne-Manneville, J.-B. Manneville, S. Nicholls , A. Ferenczi, A. Hall. 2005. Cdc42 and Par6-PKC regulate the spatially localized association of Dlg1 and APC to control cell polarization. J.Cell Biol. 170: 895-901.

N. Osmani, N. Vitale, J.-P. Borg, S. Etienne-Manneville. 2006. Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr. Biol. 16(24):2395-405.

S. Etienne-Manneville.Tumor suppressors in cell migration and invasion. 2008. Oncogene. 27(55):6970-80.

I. Dupin, E. Camand, N. Osmani, S. Etienne-Manneville. 2009. Classical cadherins control nucleus and centrosome position and cell polarity. J. Cell Biol. 185(5):779-86.

S. Etienne-Manneville. 2009. From tubulin structure to microtubule dynamics: the key players. Curr. Opin. Cell. Biol. Dec 21, Epub ahead of print.