Sandrine Etienne-Manneville

Introduction

Sandrine Etienne-Manneville’s aim is to decipher the molecular mechanisms controlling cell polarity and their implication in cell migration. She and her lab tackle this question by studying astrocyte migration. Astrocytes are major glial cells of the central nervous system. Under pathological situations involving inflammation of the cerebral tissue, astrocytes become reactive, polarize and migrate in the direction of the inflammatory site. In addition to their role in cerebral injuries, astrocytes or their progenitors can also give rise to astrocytomas and glioblastomas, the most common primary brain tumors. These tumors are associated with a very poor prognosis, mainly due to their invasive properties allowing tumor cells to escape local therapies.

Realizations

Over the last years Sandrine Etienne-Manneville and her team have investigated

1/ the role and the regulation of adherens junctions during collective migration,

2/ the regulation of Cdc42, a key evolutionary conserved regulator of cell polarity, and

3/ they have elucidated new signaling pathways controlling the organization of the cytoskeleton during cell migration.

1/ Etienne Manneville and her lab have shown for the first time that the distribution of adherens junctions was critical for front-rear polarization by controling both nucleus and centrosome positioning (Dupin et al, 2009). They have also demonstrated that N-Cadherin-mediated adherens junctions are essential regulator of directed migration and that loss of adherens junctions in gliomas contributes to the abnormal migration properties of these cells (Camand et al, 2012). They have more recently elucidated the molecular mechanisms that control maintenance and plasticity of adherens junctions during collective migration (Peglion et al, 2014).

2/ The small G proteinCdc42 is a key regulator of migrating astrocytes. The polarity protein Scrib is essential for Cdc42 localization and activation at the leading edge of migrating cells (Osmani et al, 2006). Sandrine Etienne-Manneville and her team have more recently shown Cdc42 follows an Arf6-dependent recycling that facilitates its recruitment and activation at the cell leading edge during cell migration (Osmani et al, 2010)
3/ Astrocyte migration relies on the dynamic regulation of the cytoskeleton and in particular of microtubules. They have identified a new molecular machinery responsible for microtubule anchoring and centrosome positioning during astrocyte migration (Manneville, Jehanno et al, 2010). In addition, they have highlighted the role of intermediate filaments in intracellular polarization (Dupin et al, 2011) and in directed astrocyte migration. They have identified the tumor suppressor APC (Adenomatous Polyposis Coli) as an critical binding partner of intermediate filaments involved in the reorganization of intermediate filaments during migration (Sakamoto et al, 2013). Finally, after the elucidation of the control mechanisms of the intermediate filaments network, they demonstrated the crucial role of Cdc42 in the polarisation of this network during migration initiation.