Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1

Abstract

// Caifeng Gong 1 , Julie Valduga 1, 2 , Alicia Chateau 1 , Mylène Richard 3 , Nadia Pellegrini-Moïse 3 , Muriel Barberi-Heyob 1 , Pascal Chastagner 1, 2 and Cédric Boura 1 1 Université de Lorraine, CNRS, CRAN, F-54000 Nancy, France 2 Service d'Onco-Hématologie Pédiatrique, CHRU-Nancy, F-54000 Nancy, France 3 Université de Lorraine, CNRS, L2CM, F-54000 Nancy, France Correspondence to: Cédric Boura, email: cedric.boura@univ-lorraine.fr Keywords: medulloblastoma; neuropilin-1; cancer stem cells; peptidomimetic; cell differentiation Received: July 07, 2017      Accepted: February 10, 2018      Epub: February 16, 2018      Published: March 16, 2018 ABSTRACT Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears as an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283-Med and D341-Med), classified in the more pejorative molecular subgroups, were obtained by in vitro enrichment. These models were characterized by an increase of NRP-1 and cancer stem cell markers (CD15, CD133 and Sox2), meanwhile a decrease of the differentiated cell marker Neurofilament-M (NF-M) was observed. Our previous work investigated potential innovative peptidomimetics that specifically target NRP-1 and showed that MR438 had a good affinity for NRP-1. This small molecule decreased the self-renewal capacity of MB stem cells for the 3 cell lines and reduced the invasive ability of DAOY and D283 stem cells while NRP-1 expression and cancer stem cell markers decreased at the same time. Possible molecular mechanisms were explored and showed that the activation of PI3K/AKT and MAPK pathways significantly decreased for DAOY cells after treatment. Finally, our results highlighted that targeting NRP-1 with MR438 could be a potential new strategy to differentiate MB stem cells and could limit medulloblastoma progression.