MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells
Abstract Glioblastoma (GBM) contains stem‐like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2016-04-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201505890 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849235032544116736 |
|---|---|
| author | Francesca De Bacco Antonio D'Ambrosio Elena Casanova Francesca Orzan Roberta Neggia Raffaella Albano Federica Verginelli Manuela Cominelli Pietro L Poliani Paolo Luraghi Gigliola Reato Serena Pellegatta Gaetano Finocchiaro Timothy Perera Elisabetta Garibaldi Pietro Gabriele Paolo M Comoglio Carla Boccaccio |
| author_facet | Francesca De Bacco Antonio D'Ambrosio Elena Casanova Francesca Orzan Roberta Neggia Raffaella Albano Federica Verginelli Manuela Cominelli Pietro L Poliani Paolo Luraghi Gigliola Reato Serena Pellegatta Gaetano Finocchiaro Timothy Perera Elisabetta Garibaldi Pietro Gabriele Paolo M Comoglio Carla Boccaccio |
| author_sort | Francesca De Bacco |
| collection | DOAJ |
| description | Abstract Glioblastoma (GBM) contains stem‐like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti‐apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC‐positive selection, induced by radiotherapy, into GSC eradication. |
| format | Article |
| id | doaj-art-e3a220eeaa804cb09dc87829df92d2bd |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e3a220eeaa804cb09dc87829df92d2bd2025-08-20T04:02:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-04-018555056810.15252/emmm.201505890MET inhibition overcomes radiation resistance of glioblastoma stem‐like cellsFrancesca De Bacco0Antonio D'Ambrosio1Elena Casanova2Francesca Orzan3Roberta Neggia4Raffaella Albano5Federica Verginelli6Manuela Cominelli7Pietro L Poliani8Paolo Luraghi9Gigliola Reato10Serena Pellegatta11Gaetano Finocchiaro12Timothy Perera13Elisabetta Garibaldi14Pietro Gabriele15Paolo M Comoglio16Carla Boccaccio17Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSDepartment of Molecular and Translational Medicine, Pathology Unit, University of BresciaDepartment of Molecular and Translational Medicine, Pathology Unit, University of BresciaLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSUnit of Molecular Neuro‐Oncology, Fondazione IRCCS Istituto Neurologico C. BestaUnit of Molecular Neuro‐Oncology, Fondazione IRCCS Istituto Neurologico C. BestaOctimet Oncology Ltd.Unit of Radiotherapy, Candiolo Cancer Institute, FPO‐IRCCSUnit of Radiotherapy, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSLaboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO‐IRCCSAbstract Glioblastoma (GBM) contains stem‐like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti‐apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC‐positive selection, induced by radiotherapy, into GSC eradication.https://doi.org/10.15252/emmm.201505890glioblastomaglioblastoma stem‐like cellsMET oncogeneradiosensitizationradiotherapy |
| spellingShingle | Francesca De Bacco Antonio D'Ambrosio Elena Casanova Francesca Orzan Roberta Neggia Raffaella Albano Federica Verginelli Manuela Cominelli Pietro L Poliani Paolo Luraghi Gigliola Reato Serena Pellegatta Gaetano Finocchiaro Timothy Perera Elisabetta Garibaldi Pietro Gabriele Paolo M Comoglio Carla Boccaccio MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells EMBO Molecular Medicine glioblastoma glioblastoma stem‐like cells MET oncogene radiosensitization radiotherapy |
| title | MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells |
| title_full | MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells |
| title_fullStr | MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells |
| title_full_unstemmed | MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells |
| title_short | MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells |
| title_sort | met inhibition overcomes radiation resistance of glioblastoma stem like cells |
| topic | glioblastoma glioblastoma stem‐like cells MET oncogene radiosensitization radiotherapy |
| url | https://doi.org/10.15252/emmm.201505890 |
| work_keys_str_mv | AT francescadebacco metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT antoniodambrosio metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT elenacasanova metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT francescaorzan metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT robertaneggia metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT raffaellaalbano metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT federicaverginelli metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT manuelacominelli metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT pietrolpoliani metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT paololuraghi metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT gigliolareato metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT serenapellegatta metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT gaetanofinocchiaro metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT timothyperera metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT elisabettagaribaldi metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT pietrogabriele metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT paolomcomoglio metinhibitionovercomesradiationresistanceofglioblastomastemlikecells AT carlaboccaccio metinhibitionovercomesradiationresistanceofglioblastomastemlikecells |