2. Academic Validation
  3. Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling

Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling

  • Acta Neuropathol. 2021 Sep;142(3):537-564. doi: 10.1007/s00401-021-02347-7.
Francesca Nazio  # 1,  Agnese Po 2,  Luana Abballe 1 3,  Claudio Ballabio 4,  Francesca Diomedi Camassei 5,  Matteo Bordi 1,  Antonio Camera 1,  Simona Caruso 1,  Ignazio Caruana 1,  Marco Pezzullo 1,  Caterina Ferraina 1,  Giacomo Milletti 1 6,  Matteo Gianesello 4,  Sofia Reddel 1,  Carmen Dolores De Luca 7,  Donatella Ceglie 1,  Sara Marinelli 8,  Silvia Campello 6,  Elena Papaleo 9 10,  Evelina Miele 1,  Antonella Cacchione 1,  Andrea Carai 11,  Maria Vinci 1,  Enrico Velardi 1,  Biagio De Angelis 1,  Luca Tiberi 4,  Concetta Quintarelli 1 12,  Angela Mastronuzzi 1,  Elisabetta Ferretti 3,  Franco Locatelli 1 13,  Francesco Cecconi  # 14 15 16
Affiliations

Affiliations

  • 1 Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • 2 Department of Molecular Medicine, Sapienza University, Rome, Italy.
  • 3 Department of Experimental Medicine, Sapienza University, Rome, Italy.
  • 4 Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Trento, Italy.
  • 5 Department of Laboratories, Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • 6 Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • 7 Department of Maternal and Child Health, Sapienza University of Rome, Rome, Italy.
  • 8 Consiglio Nazionale Delle Ricerche, Institute of Biochemistry and Cell Biology, Rome, Italy.
  • 9 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 10 Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark.
  • 11 Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • 12 Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
  • 13 Department of Gynecology/Obstetrics and Paediatrics, Sapienza University, Rome, Italy.
  • 14 Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. [email protected].
  • 15 Department of Biology, University of Rome Tor Vergata, Rome, Italy. [email protected].
  • 16 Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark. [email protected].
  • # Contributed equally.
PMID: 34302498 DOI: 10.1007/s00401-021-02347-7
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.

Keywords

Autophagy; Brain tumours; Cancer stem cells; Therapy.

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