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

• DOI: 10.1007/s00401-021-02347-7
• Publication Date: 2021-07-24T13:02:51Z
• Authors: Francesca Nazio; Agnese Po; Luana Abballe; Claudio Ballabio; Francesca Diomedi...; Matteo Bordi; Antonio Camera; Simona Caruso; Ignazio Caruana; Marco Pezzullo; Caterina Ferraina; Giacomo Milletti; Matteo Gianesello; Sofia Reddel; Carmen Dolores De...; Donatella Ceglie; Sara Marinelli; Silvia Campello; Elena Papaleo; Evelina Miele; Antonella Cacchione; Andrea Carai; Maria Vinci; Enrico Velardi; Biagio De Angelis; Luca Tiberi; Concetta Quintarelli; Angela Mastronuzzi; Elisabetta Ferretti; Franco Locatelli; Francesco Cecconi
• Keywords: EXPRESSION; STAT3 Transcription Factor; 570; 610; MYC; Inbred C57BL; Cell Line; ACTIVATION; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Autophagy; Animals; Humans; BRAIN; Cerebellar Neoplasms; Child; Adaptor Proteins, Signal Transducing; Original Paper; 0303 health sciences; Tumor; IDENTIFICATION; Settore BIO/06 - ANATOMIA COMPARATA E CITOLOGIA; Brain tumours; Cancer stem cells; Signal Transducing; PROLIFERATION; Adaptor Proteins; CHEMOTHERAPY; Autophagy; Brain tumours; Cancer stem cells; Therapy; Prognosis; 3. Good health; REGULATES AUTOPHAGY; Mice, Inbred C57BL; Suppressor of Cytokine Signaling 3 Protein; Gene Knockdown Techniques; medulloblastoma; ambra1; autophagy; T-CELLS; Neoplastic Stem Cells; MOLECULAR SUBGROUPS; Therapy; Autophagy; Brain tumours; Cancer stem cells; Therapy.; Medulloblastoma; Signal Transduction

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 the c-MYC oncogene (MBGroup3) have poorest prognosis. Here we identify previously unrecognized role pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that expression depends on correlates Group 3 patient poor prognosis; also, knockdown reduces stem potential, growth migration MBGroup3 cells. At molecular level, mediates these effects suppressing SOCS3, an inhibitor STAT3 activation. Importantly, pharmacological inhibition autophagy profoundly affects both invasion potential cells, combined anti-autophagy anti-STAT3 approach impacts outcome. Taken together, our data support c-MYC/AMBRA1/STAT3 axis as strong oncogenic signalling pathway significance for stratification strategies targeted treatments MBGroup3.