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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, 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 which 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 AP-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 exosomes identified miR-199a-3p as a key driver 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 exosomes 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128681 | GEO | 2019/03/22

REPOSITORIES: GEO

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