Exosomes from CD99-deprived Ewing sarcoma cells reverse tumor malignancy by inhibiting cell migration and promoting neural differentiation

Alessandra De Feo, Marika Sciandra, Manuela Ferracin, Federica Felicetti, Annalisa Astolfi, Ymera Pignochino, Piero Picci, Alessandra Carè, Katia Scotlandi

Research output: Contribution to journalArticle

Abstract

Ewing sarcoma (EWS) is an aggressive mesenchymal tumor with unmet clinical need and significant social impacts on children, adolescents, and young adults. CD99, a hallmark surface molecule of EWS, participates in crucial biological processes including cell migration, differentiation, and death. EWS cells can release CD99 through exosomes (EXOs), specialized extracellular vesicles with major cell communication roles. Here we show that, as a consequence of CD99 silencing, EWS cells deliver exosomes with oncosuppressive functions that significantly reduce tumor aggressiveness. These CD99-lacking microvesicles modulate gene expression of the EWS-recipient cells, reduce proliferation and migration, in turn inducing a more-differentiated less-malignant phenotype. The most relevant effects were detected on the activator protein-1 signaling pathway whose regulation was found to be dependent on the specific cargo loaded in vesicles after CD99 shutdown. Investigation of the miRNA content of CD99-deprived EXOs identified miR-199a-3p as a key driver able to reverse EWS malignancy in experimental models as well as in clinical specimens. All together, our data provide evidence that the abrogation of CD99 in EWS tumor cells leads to produce and release EXOs capable to transfer their antineoplastic effects into the nearby tumor cells, suggesting a novel atypical role for these microvesicles in reversion of malignancy rather than in priming the soil for progression and metastatic seeding. This conceptually innovative approach might offer a new therapeutic opportunity to treat a tumor still refractory to most treatments.

Original languageEnglish
Number of pages15
JournalCell death & disease
Volume10
Issue number7
DOIs
Publication statusPublished - Jun 17 2019

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Exosomes
Ewing's Sarcoma
Cell Movement
Neoplasms
Biological Phenomena
Transcription Factor AP-1
Social Change
MicroRNAs
Cell Communication
Antineoplastic Agents
Cell Differentiation
Young Adult
Cell Death
Theoretical Models
Soil
Cell Proliferation
Phenotype
Gene Expression

Cite this

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title = "Exosomes from CD99-deprived Ewing sarcoma cells reverse tumor malignancy by inhibiting cell migration and promoting neural differentiation",
abstract = "Ewing sarcoma (EWS) is an aggressive mesenchymal tumor with unmet clinical need and significant social impacts on children, adolescents, and young adults. CD99, a hallmark surface molecule of EWS, participates in crucial biological processes including cell migration, differentiation, and death. EWS cells can release CD99 through exosomes (EXOs), specialized extracellular vesicles with major cell communication roles. Here we show that, as a consequence of CD99 silencing, EWS cells deliver exosomes with oncosuppressive functions that significantly reduce tumor aggressiveness. These CD99-lacking microvesicles modulate gene expression of the EWS-recipient cells, reduce proliferation and migration, in turn inducing a more-differentiated less-malignant phenotype. The most relevant effects were detected on the activator protein-1 signaling pathway whose regulation was found to be dependent on the specific cargo loaded in vesicles after CD99 shutdown. Investigation of the miRNA content of CD99-deprived EXOs identified miR-199a-3p as a key driver able to reverse EWS malignancy in experimental models as well as in clinical specimens. All together, our data provide evidence that the abrogation of CD99 in EWS tumor cells leads to produce and release EXOs capable to transfer their antineoplastic effects into the nearby tumor cells, suggesting a novel atypical role for these microvesicles in reversion of malignancy rather than in priming the soil for progression and metastatic seeding. This conceptually innovative approach might offer a new therapeutic opportunity to treat a tumor still refractory to most treatments.",
author = "{De Feo}, Alessandra and Marika Sciandra and Manuela Ferracin and Federica Felicetti and Annalisa Astolfi and Ymera Pignochino and Piero Picci and Alessandra Car{\`e} and Katia Scotlandi",
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T1 - Exosomes from CD99-deprived Ewing sarcoma cells reverse tumor malignancy by inhibiting cell migration and promoting neural differentiation

AU - De Feo, Alessandra

AU - Sciandra, Marika

AU - Ferracin, Manuela

AU - Felicetti, Federica

AU - Astolfi, Annalisa

AU - Pignochino, Ymera

AU - Picci, Piero

AU - Carè, Alessandra

AU - Scotlandi, Katia

PY - 2019/6/17

Y1 - 2019/6/17

N2 - Ewing sarcoma (EWS) is an aggressive mesenchymal tumor with unmet clinical need and significant social impacts on children, adolescents, and young adults. CD99, a hallmark surface molecule of EWS, participates in crucial biological processes including cell migration, differentiation, and death. EWS cells can release CD99 through exosomes (EXOs), specialized extracellular vesicles with major cell communication roles. Here we show that, as a consequence of CD99 silencing, EWS cells deliver exosomes with oncosuppressive functions that significantly reduce tumor aggressiveness. These CD99-lacking microvesicles modulate gene expression of the EWS-recipient cells, reduce proliferation and migration, in turn inducing a more-differentiated less-malignant phenotype. The most relevant effects were detected on the activator protein-1 signaling pathway whose regulation was found to be dependent on the specific cargo loaded in vesicles after CD99 shutdown. Investigation of the miRNA content of CD99-deprived EXOs identified miR-199a-3p as a key driver able to reverse EWS malignancy in experimental models as well as in clinical specimens. All together, our data provide evidence that the abrogation of CD99 in EWS tumor cells leads to produce and release EXOs capable to transfer their antineoplastic effects into the nearby tumor cells, suggesting a novel atypical role for these microvesicles in reversion of malignancy rather than in priming the soil for progression and metastatic seeding. This conceptually innovative approach might offer a new therapeutic opportunity to treat a tumor still refractory to most treatments.

AB - Ewing sarcoma (EWS) is an aggressive mesenchymal tumor with unmet clinical need and significant social impacts on children, adolescents, and young adults. CD99, a hallmark surface molecule of EWS, participates in crucial biological processes including cell migration, differentiation, and death. EWS cells can release CD99 through exosomes (EXOs), specialized extracellular vesicles with major cell communication roles. Here we show that, as a consequence of CD99 silencing, EWS cells deliver exosomes with oncosuppressive functions that significantly reduce tumor aggressiveness. These CD99-lacking microvesicles modulate gene expression of the EWS-recipient cells, reduce proliferation and migration, in turn inducing a more-differentiated less-malignant phenotype. The most relevant effects were detected on the activator protein-1 signaling pathway whose regulation was found to be dependent on the specific cargo loaded in vesicles after CD99 shutdown. Investigation of the miRNA content of CD99-deprived EXOs identified miR-199a-3p as a key driver able to reverse EWS malignancy in experimental models as well as in clinical specimens. All together, our data provide evidence that the abrogation of CD99 in EWS tumor cells leads to produce and release EXOs capable to transfer their antineoplastic effects into the nearby tumor cells, suggesting a novel atypical role for these microvesicles in reversion of malignancy rather than in priming the soil for progression and metastatic seeding. This conceptually innovative approach might offer a new therapeutic opportunity to treat a tumor still refractory to most treatments.

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