Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma
Abstract Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most l...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01679-7 |
| _version_ | 1797555813678579712 |
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| author | Elena Mariotto Elena Rampazzo Roberta Bortolozzi Fatlum Rruga Ilaria Zeni Lorenzo Manfreda Chiara Marchioro Martina Canton Alice Cani Ruben Magni Alessandra Luchini Silvia Bresolin Giampietro Viola Luca Persano |
| author_facet | Elena Mariotto Elena Rampazzo Roberta Bortolozzi Fatlum Rruga Ilaria Zeni Lorenzo Manfreda Chiara Marchioro Martina Canton Alice Cani Ruben Magni Alessandra Luchini Silvia Bresolin Giampietro Viola Luca Persano |
| author_sort | Elena Mariotto |
| collection | DOAJ |
| description | Abstract Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting. |
| first_indexed | 2024-03-10T16:52:57Z |
| format | Article |
| id | doaj.art-72f58709d4e748608303fe94f6b17b4c |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-10T16:52:57Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-72f58709d4e748608303fe94f6b17b4c2023-11-20T11:14:57ZengBMCActa Neuropathologica Communications2051-59602023-11-0111111610.1186/s40478-023-01679-7Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastomaElena Mariotto0Elena Rampazzo1Roberta Bortolozzi2Fatlum Rruga3Ilaria Zeni4Lorenzo Manfreda5Chiara Marchioro6Martina Canton7Alice Cani8Ruben Magni9Alessandra Luchini10Silvia Bresolin11Giampietro Viola12Luca Persano13Department of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaCenter for Applied Proteomics and Molecular Medicine, George Mason UniversityCenter for Applied Proteomics and Molecular Medicine, George Mason UniversityDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaDepartment of Women’s and Children’s Health, University of PadovaAbstract Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting.https://doi.org/10.1186/s40478-023-01679-7Chemotherapy resistanceMedulloblastomaHigh throughput drug screeningAntimetabolites |
| spellingShingle | Elena Mariotto Elena Rampazzo Roberta Bortolozzi Fatlum Rruga Ilaria Zeni Lorenzo Manfreda Chiara Marchioro Martina Canton Alice Cani Ruben Magni Alessandra Luchini Silvia Bresolin Giampietro Viola Luca Persano Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma Acta Neuropathologica Communications Chemotherapy resistance Medulloblastoma High throughput drug screening Antimetabolites |
| title | Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma |
| title_full | Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma |
| title_fullStr | Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma |
| title_full_unstemmed | Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma |
| title_short | Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma |
| title_sort | molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism dependent vulnerabilities in medulloblastoma |
| topic | Chemotherapy resistance Medulloblastoma High throughput drug screening Antimetabolites |
| url | https://doi.org/10.1186/s40478-023-01679-7 |
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