CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

Maria Cristina Manara, M. Terracciano, Caterina Mancarella, Marika Sciandra, Clara Guerzoni, Michela Pasello, A. Grilli, Nicoletta Zini, Piero Picci, Mario Paolo Colombo, Andrea Morrione, Katia Scotlandi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)79925-79942
Number of pages18
JournalOncotarget
Volume7
Issue number48
DOIs
Publication statusPublished - 2016

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Keywords

  • Antibody
  • CD99
  • Cell death
  • Ewing sarcoma
  • RAS

ASJC Scopus subject areas

  • Oncology

Cite this

Manara, M. C., Terracciano, M., Mancarella, C., Sciandra, M., Guerzoni, C., Pasello, M., Grilli, A., Zini, N., Picci, P., Colombo, M. P., Morrione, A., & Scotlandi, K. (2016). CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling. Oncotarget, 7(48), 79925-79942. https://doi.org/10.18632/oncotarget.13160