Structural Decoding of the Netrin-1/UNC5 Interaction and its Therapeutical Implications in Cancers
Melodie Grandin, Markus Meier, Jean Guy Delcros, Denise Nikodemus, Raphael Reuten, Trushar R Patel, David Goldschneider, George Orriss, Natalie Krahn, Amina Boussouar, Riad Abes, Yann Dean, David Neves, Agnes Bernet, Stephane Depil, Fiona Schneiders, Kate Poole, Robert Dante, Manuel Koch, Patrick Mehlen Show all
Cancer Cell | CELL PRESS | Published : 2016
Netrin-1 has been shown to be up-regulated in a fraction of human cancers as a mechanism to allow these tumors to escape the pro-apoptotic activity of some of its main dependence receptors, the UNC5 homologs (UNC5H). Here we identify the V-2 domain of netrin-1 to be important for its interaction with the Ig1/Ig2 domains of UNC5H2. We generate a humanized anti-netrin-1 antibody that disrupts the interaction between netrin-1 and UNC5H2 and triggers death of netrin-1-expressing tumor cells in vitro. We also present evidence that combining the anti-netrin-1 antibody with epidrugs such as decitabine could be effective in treating tumors showing no or modest netrin-1 expression. These results supp..View full abstract
Awarded by Canadian Institute of Health Research
Awarded by Deutsche Forschungsgemeinschaft
We thank C. Schulze-Briese (SLS, Switzerland), P. Grochulski (CLS, Canada), and M. Bekker (APS, USA) for assistance in data collection; S. Oezcelik and A. Paradisi for technical support and S. McKenna and S. Oezbek for critical reading and discussions. J.S. is funded in part by the Multiple Sclerosis Society of Canada and by the Canadian Institute of Health Research (RPA-109759), and M.K. is funded by the Deutsche Forschungsgemeinschaft SFB 829 grant A2 and by the Koln Fortune Programm of the Medical Faculty. This work was also supported by Netris Pharma and institutional grants from CNRS (P. M.), University of Lyon (P. M.), Center Leon Berard (P. M.), and from the Ligue Contre le Cancer (P. M.), INCA (P. M.), ANR (P. M.), ERC (P. M.), EU-FP7 HERMIONE-2MAN (P. M.), and Fondation Bettencourt (P. M.). K.P. is supported by the Cecile Vogt Fellowship, and T.R.P. was supported as a CIHR Postdoctoral Fellow. J.S. is a Canada Research Chair in Structural Biology.