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.
Highlights
Ewing sarcoma (EWS) is a malignant mesenchymal tumor of children and young adults, with unmet clinical solution and relevant social impact
CD99 triggering by 0662mAb induces massive macropinocytosis that results in cell death
Mitochondria and the double membrane typical of autophagosomes were rarely observed, suggesting that CD99-associated cell death might be related to methuosis [12], which is characterized by progressive accumulation of cytoplasmic vacuoles originating from macro- and/or micro-pinosomes [25]
Summary
Ewing sarcoma (EWS) is a malignant mesenchymal tumor of children and young adults, with unmet clinical solution and relevant social impact. Metastatic patients have very poor prognosis and treatment remains a challenge. As a transcription factor, EWS–FLI1 is a puzzling drug target [4], and current therapy of EWS still depends on conventional cytotoxic drugs with no alternative options for patients relapsing after first line therapies. This is www.impactjournals.com/oncotarget relevant being EWS generally resistant to apoptotic cell death. The identification of novel mechanisms inducing cell death independently of canonical apoptosis is imperative for developing new therapeutic approaches for EWS patients
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