Semaphorin 3E Suppresses Tumor Cell Death Triggered by the Plexin D1 Dependence Receptor in Metastatic Breast Cancers
Menée à l'aide de modèles murins de cancer métastatique du sein, cette étude met en évidence des mécanismes par lesquels la sémaphorine 3E régule la survie des cellules tumorales
The semaphorin guidance molecules and their receptors, the plexins, are often inappropriately expressed in cancers. However, the signaling processes mediated by plexins in tumor cells are still poorly understood. Here, we demonstrate that the Semaphorin 3E (Sema3E) regulates tumor cell survival by suppressing an apoptotic pathway triggered by the Plexin D1 dependence receptor. In mouse models of breast cancer, a ligand trap that sequesters Sema3E inhibited tumor growth and reduced metastasis through a selective tumor cytocidal effect. We further showed that Plexin D1 triggers apoptosis via interaction with the orphan nuclear receptor NR4A1. These results define a critical role of Sema3E/Plexin D1 interaction in tumor resistance to apoptosis and suggest a therapeutic approach based on activation of a dependence receptor pathway. "Plexin D1 is a member of the dependence receptor family "The Plexin D1 ligand Sema3E is a tumor cell autonomous survival factor "A soluble Plexin D1 ligand trap induces NR4A1-mediated apoptosis of tumor cells "A soluble Plexin D1 ligand trap reduces tumor growth and metastasis