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SUMMARY:Polarity reversal during epithelial-to-mesenchymal transition - Dr
  Manuel Thery\, Hospital Saint Louis\, Paris\, France
DTSTART:20151008T150000Z
DTEND:20151008T160000Z
UID:TALK58061@talks.cam.ac.uk
CONTACT:16026
DESCRIPTION:Epithelial to mesenchymal transition (EMT) is a morphogenetic 
 event that takes place during specific stages of embryo development and ea
 rly stages of tumour dissemination. Proper tissue functions strongly depen
 d on the establishment of cell polarity. Epithelial\, non-motile cells est
 ablish an apico-basal polarity whereas mesenchymal\, migrating cells displ
 ay a front-rear polarity. Polarized distributions of cell-cell and cell-ma
 trix adhesions direct the asymmetric spatial organization of cell internal
  compartments to establish cell polarity. Cell adhesions remodelling being
  central to EMT\, we hypothesized it was coupled to polarity changes. We m
 onitored centrosome positioning during EMT since it is a central regulator
  of cell polarity. Indeed\, it defines microtubules network architecture a
 nd thereby orients internal traffic. First\, we observed that EMT inductio
 n by TGFcauses disorganization of cells in 3D epithelial cell cultur
 es along with the loss of centrosome localization to apical side. To under
 stand whether centrosome mislocalization was a driver of EMT or a conseque
 nce of cells disorganization\, we used a minimal model of tissue comprisin
 g two cells whose positions were controlled on a micropattern. We found th
 at nucleus-centrosome axis was preferentially orientated to the cell-cell 
 junction in epithelial cell pair. Few hours following the addition of EMT 
 inducers\, the cells in the very early stages of EMT were detected to unde
 rgo polarity reversal by centrosome repositioning toward cell-ECM adhesion
 s. This phenomenon was more pronounced under prolonged presence of EMT ind
 ucer over 3-5 days. This process could be confirmed in three different epi
 thelial cell types. Centrosome repositioning could be reverted in epitheli
 al and mesenchymal states by the modulation of the expression levels of Pa
 r3\, which is a polarity complex protein localized to cell-cell junctions.
  In parallel\, polarity reversal was associated with re-distribution of ce
 ll-cell and cell-ECM traction forces. Increase in traction forces compared
  to intercellular forces in mesenchymal cells seemed to prime them for sca
 ttering. Finally\, we demonstrated that centrosome repositioning during EM
 T directly induces the scattering of mesenchymal cells with the help of dy
 namic surface coating to control cell release from micropatterns. Indeed c
 entrosome repositioning was required for mesenchymal cell to separate and 
 migrate away from each other. Preliminary observations in developing mouse
  mammary gland and early mouse embryo suggested polarity reversal was actu
 ally instrumental in physiological EMT. These findings demonstrate that up
 on onset of EMT\, epithelial cells execute a polarity reversal program by 
 centrosome repositioning which is necessary for the scattering of resultin
 g mesenchymal cells.\n
LOCATION:Hodgkin Huxley Seminar Room\, Physiology Building\, Downing Site
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