CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling.
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.
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Maria Cristina
MC
Manara
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.|Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Mario
M
Terracciano
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Caterina
C
Mancarella
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.|PROMETEO Laboratory, STB, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Marika
M
Sciandra
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.|PROMETEO Laboratory, STB, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Clara
C
Guerzoni
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.|PROMETEO Laboratory, STB, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Michela
M
Pasello
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Andrea
A
Grilli
CNR, National Research Council of Italy, Institute of Molecular Genetics, Bologna 40136, Italy.|SC Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Nicoletta
N
Zini
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.|PROMETEO Laboratory, STB, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Piero
P
Picci
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS "Istituto Nazionale dei Tumori," Milan 20133, Italy.
Mario P
MP
Colombo
Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Andrea
A
Morrione
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.|PROMETEO Laboratory, STB, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Katia
K
Scotlandi
D000071443:12E7 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D011905:Genes, ras / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D010873:Pinocytosis / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000071443:12E7 Antigen; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; C061828:CD99 protein, human; C000597236:IGF1R protein, human; C107953:RAC1 protein, human; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1; D020830:rac1 GTP-Binding Protein
CD99; Ewing sarcoma; RAS; antibody; cell death