CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling
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Maria Cristina Manara1, Mario Terracciano1,6, Caterina Mancarella1, Marika Sciandra1,2, Clara Guerzoni1,2, Michela Pasello1,2, Andrea Grilli1, Nicoletta Zini3,4, Piero Picci1,2, Mario P. Colombo5, Andrea Morrione6, Katia Scotlandi1,2
1CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy
2PROMETEO Laboratory, STB, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy
3CNR, National Research Council of Italy, Institute of Molecular Genetics, Bologna 40136, Italy
4SC Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, Bologna 40136, Italy
5Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS “Istituto Nazionale dei Tumori,” Milan 20133, Italy
6Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Katia Scotlandi, email: email@example.com
Andrea Morrione, email: Andrea.Morrione@jefferson.edu
Keywords: antibody, CD99, cell death, Ewing sarcoma, RAS
Received: August 12, 2016 Accepted: October 14, 2016 Published: November 07, 2016
CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.
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