Abstract

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MBGroup3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MBGroup3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3.

Details

Title
Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling
Author
Nazio Francesca 1 ; Po Agnese 2 ; Abballe Luana 3 ; Ballabio Claudio 4 ; Diomedi, Camassei Francesca 5 ; Bordi Matteo 1 ; Camera, Antonio 1 ; Caruso, Simona 1 ; Caruana Ignazio 1 ; Pezzullo, Marco 1 ; Ferraina Caterina 1 ; Milletti Giacomo 6 ; Gianesello Matteo 4 ; Reddel Sofia 1 ; De Luca Carmen Dolores 7 ; Ceglie Donatella 1 ; Marinelli, Sara 8 ; Campello, Silvia 9 ; Papaleo, Elena 10 ; Miele Evelina 1 ; Cacchione Antonella 1 ; Carai, Andrea 11 ; Vinci, Maria 1 ; Velardi Enrico 1 ; De Angelis Biagio 1 ; Tiberi Luca 4 ; Quintarelli Concetta 12 ; Mastronuzzi, Angela 1 ; Ferretti Elisabetta 13 ; Locatelli, Franco 14 ; Cecconi, Francesco 15   VIAFID ORCID Logo 

1  Bambino Gesù Children’s Hospital, IRCCS, Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809) 
2  Sapienza University, Department of Molecular Medicine, Rome, Italy (GRID:grid.7841.a) 
3  Bambino Gesù Children’s Hospital, IRCCS, Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809); Sapienza University, Department of Experimental Medicine, Rome, Italy (GRID:grid.7841.a) 
4  University of Trento, Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, Trento, Italy (GRID:grid.11696.39) (ISNI:0000 0004 1937 0351) 
5  Bambino Gesù Children’s Hospital, IRCCS, Department of Laboratories, Pathology Unit, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809) 
6  Bambino Gesù Children’s Hospital, IRCCS, Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809); University of Rome Tor Vergata, Department of Biology, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941) 
7  Sapienza University of Rome, Department of Maternal and Child Health, Rome, Italy (GRID:grid.7841.a) 
8  Consiglio Nazionale Delle Ricerche, Institute of Biochemistry and Cell Biology, Rome, Italy (GRID:grid.5326.2) (ISNI:0000 0001 1940 4177) 
9  University of Rome Tor Vergata, Department of Biology, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941) 
10  Danish Cancer Society Research Center, Computational Biology Laboratory, Copenhagen, Denmark (GRID:grid.417390.8) (ISNI:0000 0001 2175 6024); Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
11  Bambino Gesù Children’s Hospital, IRCCS, Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809) 
12  Bambino Gesù Children’s Hospital, IRCCS, Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809); University of Naples Federico II, Department of Translational Medical Sciences, Naples, Italy (GRID:grid.4691.a) (ISNI:0000 0001 0790 385X) 
13  Sapienza University, Department of Experimental Medicine, Rome, Italy (GRID:grid.7841.a) 
14  Bambino Gesù Children’s Hospital, IRCCS, Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809); Sapienza University, Department of Gynecology/Obstetrics and Paediatrics, Rome, Italy (GRID:grid.7841.a) 
15  Bambino Gesù Children’s Hospital, IRCCS, Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809); University of Rome Tor Vergata, Department of Biology, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941); Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark (GRID:grid.417390.8) (ISNI:0000 0001 2175 6024) 
Pages
537-564
Publication year
2021
Publication date
Sep 2021
Publisher
Springer Nature B.V.
ISSN
00016322
e-ISSN
14320533
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1007/s00401-021-02347-7
ProQuest document ID
2560163293
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.