Journal Article Epublish 8 citations
PubMed: 36457009 DOI: 10.1186/s12935-022-02796-4
NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells.
Cancer Cell Int 22(1):377
Authors: Manon Douyère, Caifeng Gong, Mylène Richard, Nadia Pellegrini-Moïse, Joël Daouk, Julien Pierson, Pascal Chastagner, Cédric Boura
Affiliations
- Université de Lorraine, CNRS, CRAN, UMR 7039, 54000, Nancy, France.
- Université de Lorraine, CNRS, CRAN, UMR 7039, 54000, Nancy, France. Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Can-Cer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Bei-Jing, 100021, China.
- Université de Lorraine, CNRS, L2CM, UMR 7053, Campus Science, 54500, Vandœuvre-Lès-Nancy, France.
- Service d'Onco-Hématologie Pédiatrique, CHRU-Nancy, 54000, Nancy, France.
- Université de Lorraine, CNRS, CRAN, UMR 7039, 54000, Nancy, France.
Abstract
BACKGROUND
Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Despite current therapies, the morbidity and recurrent risk remains significant. Neuropilin-1 receptor (NRP1) has been implicated in the tumor progression of MB. Our recent study showed that NRP1 inhibition stimulated MB stem cells differentiation. Consequently, we hypothesized that targeting NRP1 in medulloblastoma could improve current treatments.
METHODS
NRP1 inhibition with a novel peptidomimetic agent, MR438, was evaluated with radiotherapy (RT) in MB models (DAOY, D283-Med and D341-Med) in vitro on cancer stem-like cells as well as in vivo on heterotopic and orthotopic xenografts.
RESULTS
We show that NRP1 inhibition by MR438 radiosensitizes MB stem-like cells in vitro. In heterotopic DAOY models, MR438 improves RT efficacy as measured by tumor growth and mouse survival. In addition, clonogenic assays after tumor dissociation showed a significant reduction in cancer stem cells with the combination treatment. In the same way, a benefit of the combined therapy was observed in the orthotopic model only for a low cumulative irradiation dose of 10 Gy but not for 20 Gy.
CONCLUSIONS
Finally, our results demonstrated that targeting NRP1 with MR438 could be a potential new strategy and could limit MB progression by decreasing the stem cell number while reducing the radiation dose.
MeSH
Cells, Radiation Tolerance, Microscopy, Electron, Scanning Transmission, Neoplasms, Stem Cells, Medulloblastoma, Therapeutics
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