NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-022-02796-4 |
| _version_ | 1811190262839377920 |
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| author | Manon Douyère Caifeng Gong Mylène Richard Nadia Pellegrini-Moïse Joël Daouk Julien Pierson Pascal Chastagner Cédric Boura |
| author_facet | Manon Douyère Caifeng Gong Mylène Richard Nadia Pellegrini-Moïse Joël Daouk Julien Pierson Pascal Chastagner Cédric Boura |
| author_sort | Manon Douyère |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T14:48:14Z |
| format | Article |
| id | doaj.art-857627dcf9454b46b41d1d1aa89c0a18 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-04-11T14:48:14Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-857627dcf9454b46b41d1d1aa89c0a182022-12-22T04:17:34ZengBMCCancer Cell International1475-28672022-12-0122111410.1186/s12935-022-02796-4NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cellsManon Douyère0Caifeng Gong1Mylène Richard2Nadia Pellegrini-Moïse3Joël Daouk4Julien Pierson5Pascal Chastagner6Cédric Boura7Université de Lorraine, CNRS, CRAN, UMR 7039Université de Lorraine, CNRS, CRAN, UMR 7039Université de Lorraine, CNRS, L2CM, UMR 7053Université de Lorraine, CNRS, L2CM, UMR 7053Université de Lorraine, CNRS, CRAN, UMR 7039Université de Lorraine, CNRS, CRAN, UMR 7039Université de Lorraine, CNRS, CRAN, UMR 7039Université de Lorraine, CNRS, CRAN, UMR 7039Abstract 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.https://doi.org/10.1186/s12935-022-02796-4MedulloblastomaNeuropilin-1Cancer stem cellsRadiotherapy |
| spellingShingle | Manon Douyère Caifeng Gong Mylène Richard Nadia Pellegrini-Moïse Joël Daouk Julien Pierson Pascal Chastagner Cédric Boura NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells Cancer Cell International Medulloblastoma Neuropilin-1 Cancer stem cells Radiotherapy |
| title | NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells |
| title_full | NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells |
| title_fullStr | NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells |
| title_full_unstemmed | NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells |
| title_short | NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells |
| title_sort | nrp1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells |
| topic | Medulloblastoma Neuropilin-1 Cancer stem cells Radiotherapy |
| url | https://doi.org/10.1186/s12935-022-02796-4 |
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