Frontiers in Oncology (Apr 2022)
MET Inhibition Sensitizes Rhabdomyosarcoma Cells to NOTCH Signaling Suppression
- Clara Perrone,
- Clara Perrone,
- Silvia Pomella,
- Matteo Cassandri,
- Matteo Cassandri,
- Michele Pezzella,
- Giuseppe Maria Milano,
- Marta Colletti,
- Cristina Cossetti,
- Giulia Pericoli,
- Angela Di Giannatale,
- Emmanuel de Billy,
- Maria Vinci,
- Stefania Petrini,
- Francesco Marampon,
- Concetta Quintarelli,
- Concetta Quintarelli,
- Riccardo Taulli,
- Josep Roma,
- Soledad Gallego,
- Simona Camero,
- Paolo Mariottini,
- Manuela Cervelli,
- Roberta Maestro,
- Lucio Miele,
- Biagio De Angelis,
- Franco Locatelli,
- Franco Locatelli,
- Rossella Rota
Affiliations
- Clara Perrone
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Clara Perrone
- Department of Science, “Department of Excellence 2018-2022”, University of Rome “Roma Tre”, Rome, Italy
- Silvia Pomella
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Matteo Cassandri
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Matteo Cassandri
- Department of Radiotherapy, Sapienza University, Rome, Italy
- Michele Pezzella
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Giuseppe Maria Milano
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Marta Colletti
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Cristina Cossetti
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Giulia Pericoli
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Angela Di Giannatale
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Emmanuel de Billy
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Maria Vinci
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Stefania Petrini
- Confocal Microscopy Core Facility, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Francesco Marampon
- Department of Radiotherapy, Sapienza University, Rome, Italy
- Concetta Quintarelli
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Concetta Quintarelli
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Riccardo Taulli
- Department of Oncology, University of Torino, Torino, Italy
- Josep Roma
- Group of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Insti-tute-Universitat Autònoma de Barcelona, Barcelona, Spain
- Soledad Gallego
- Group of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Insti-tute-Universitat Autònoma de Barcelona, Barcelona, Spain
- Simona Camero
- Department of Maternal, Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
- Paolo Mariottini
- Department of Science, “Department of Excellence 2018-2022”, University of Rome “Roma Tre”, Rome, Italy
- Manuela Cervelli
- Department of Science, “Department of Excellence 2018-2022”, University of Rome “Roma Tre”, Rome, Italy
- Roberta Maestro
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
- Lucio Miele
- 0Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Biagio De Angelis
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Franco Locatelli
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Franco Locatelli
- 1Department of Pediatrics, Sapienza University, Rome, Italy
- Rossella Rota
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- DOI
- https://doi.org/10.3389/fonc.2022.835642
- Journal volume & issue
-
Vol. 12
Abstract
Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy. Therefore, novel therapeutic approaches are needed to halt tumor progression. NOTCH signaling has oncogenic functions in RMS and its pharmacologic inhibition through γ-secretase inhibitors blocks tumor growth in vitro and in vivo. Here, we show that NOTCH signaling blockade resulted in the up-regulation and phosphorylation of the MET oncogene in both RH30 (FP-RMS) and RD (FN-RMS) cell lines. Pharmacologic inhibition of either NOTCH or MET signaling slowed proliferation and restrained cell survival compared to control cells partly by increasing Annexin V and CASP3/7 activation. Co-treatment with NOTCH and MET inhibitors significantly amplified these effects and enhanced PARP1 cleavage in both cell lines. Moreover, it severely hampered cell migration, colony formation, and anchorage-independent growth compared to single-agent treatments in both cell lines and significantly prevented the growth of FN-RMS cells grown as spheroids. Collectively, our results unveil the overexpression of the MET oncogene by NOTCH signaling targeting in RMS cells and show that MET pathway blockade sensitizes them to NOTCH inhibition.
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