CD133 structural instability as a gateway to medulloblastoma vulnerability.

Authors

Zaira Spinello, Martina Brunetti, Natalia Pediconi, Sofia Trocchianesi, Laura Giusti, Luana Abballe, Laura Masuelli, Roberto Bei, Evelina Miele, Agnese Po, Anna Citarella, Giacomo Ruggiero, Federica Di Cintio, Andrea Ragusa, Angela Mastronuzzi, Franco Locatelli, Elisabetta Ferretti, Maurizio Ronci, Giuseppina Catanzaro

Published in

Cancer cell international. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Medulloblastoma (MB) is the most common malignant paediatric brain tumor. Among distinct MB subtypes, Group 3 represents one of the most aggressive subtypes, with high relapse rate, frequent metastasis, and mortality. These malignant traits are largely driven by MB stem cells (MBSCs), a subpopulation with enhanced self-renewal capacity and resistance to standard therapies, making them prime targets for innovative treatment strategies.
Group 3 MB human cell lines were treated with 0.3 µM Brefeldin A (BFA), a potent inducer of endoplasmic reticulum stress. Proteomic analyses via nano-LC-MS/MS were employed to investigate structural alterations in CD133, a key cell surface and stemness-associated receptor. Finally, computational screening was performed to identify Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved compounds, with improved pharmacokinetic and pharmacodynamic profiles that mimic BFA's mechanism of action.
We demonstrate that BFA induced structural disruption of CD133 and compromised MBSCs stem-like phenotype. This loss of stem-like properties correlates with diminished clonogenic potential, downregulation of the oncogenic PI3K/AKT/mTOR signaling axis, and impaired intercellular communication. Importantly, we identified clinically approved compounds capable of recapitulating the biological effects associated with BFA treatment.
This study uncovers a previously unrecognized mechanism of CD133 structural modulation and highlights the existence of clinically approved compounds that may impair MBSC function, offering a promising possible avenue for targeting therapy-resistant tumor-initiating cells in aggressive Group 3 MB.

PMID:
42443895
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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