Decoding the netrin-1/UNC5 interaction and its therapeutical implications in cancers
 | Figure:
Surface rendering of the netrin-1/UNC5H complex and schematic diagram
of the chemoattraction and chemorepulsion functions of netrin-1.
|
Joerg Stetefeld group (University of Manitoba)
The group of Joerg Stetefeld determined an important
structure in the battle against cancer. Along with collaborators at
the University of Cologne and the CNRS in Lyon, the investigators aimed
to unravel the molecular mechanism of the Netrin-1/UNC5H interaction.
Netrin-1 is a bifunctional guidance cue that regulates the adhesion,
migration and survival of cells through its interaction with dependence
receptors and orchestrates chemoattraction (via NEO1/DCC), as well as
chemorepulsion (via UNC5H). Netrin-1 is up-regulated in a fraction of
human cancers as a mechanism to block the pro-apoptotic activity of the
UNC5H receptors. Stetefeld and colleagues identified in atomic detail
the UNC5H-binding epitope of netrin-1 and identified an antibody
targeting netrin-1 and disrupting the UNC5H interaction. The antibody
has therapeutic potential both in solid tumors and in hematological
malignancies, and clinical trials will begin this year.
Citation: Grandin M, Meier M, Delcros JG, Nikodemus D,
Reuten R, Patel TR, Goldschneider D, Orriss G, Krahn N, Boussouar A,
Abes R, Dean Y, Neves D, Bernet A, Depil S, Schneiders F, Poole K,
Dante R, Koch M, Mehlen P, and Stetefeld J. Structural decoding
of the netrin-1/UNC5 interaction and its therapeutical implications in
cancers. (2016) Cancer Cell 29, 173-185.
|