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CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling
Manara, Maria Cristina Terracciano, Mario Mancarella, Caterina Sciandra, Marika Guerzoni, Clara Pasello, Michela Grilli, Andrea Zini, Nicoletta Picci, Piero Colombo, Mario P.
Manara, Maria Cristina
Terracciano, Mario
Mancarella, Caterina
Sciandra, Marika
Guerzoni, Clara
Pasello, Michela
Grilli, Andrea
Zini, Nicoletta
Picci, Piero
Colombo, Mario P.
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Journal article
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2016-11-07
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Biology
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https://doi.org/10.18632/oncotarget.13160
Abstract
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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Manara M., Terracciano M., Mancarella C., Sciandra M., Guerzoni C., Pasello M., Grilli A., Zini N., Picci P., Colombo M. P., Morrione A., Scotlandi K. CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling. Oncotarget. 2016; 7: 79925-79942. Retrieved from https://www.oncotarget.com/article/13160/text/
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Oncotarget, Vol. 7, No. 48
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