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Open Access 01-12-2023 | Medulloblastoma | Research

Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma

Authors: 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

Published in: Acta Neuropathologica Communications | Issue 1/2023

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.

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Title: Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma
Authors: 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
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Medulloblastoma
Medulloblastoma
Medulloblastoma
Antimetabolite
Cytostatic Therapy
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01679-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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