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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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CD99 inhibits neural differentiation of human Ewing sarcoma cells

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2015-02-01 | E-GEOD-36097 | biostudies-arrayexpress

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Project description:CD99 is a transmembrane protein, whose expression is constantly associated to Ewing’s Sarcoma (EWS), a class of pediatric bone tumors with particular poor prognosis. We previously reported that engagement of CD99 leads to massive and rapid EWS cell death through a non-canonical path. Here we report that death occurs through a novel mechanism starting from classical apoptotic features, such as phosphatydilserine exposure on cell surface and mitochondrial depolarization and ending with massive cytoplasmic hypervacuolization (autophagosomes and micropinosomes). Mechanistically, CD99 induces upregulation of IGFI-R and RAS and rapid MDM2 degradation, which leads to p53 reactivation. We propose that upon CD99 engagement and subsequent p53 reactivation, the EWS-ets oncogene becomes insufficient to sustain EWS transformation; in this context, up-regulated RAS, deprived of a cooperating oncogenic stimulus, might contribute to the delivery of fatal rather than pro-survival signal. The most CD99-responsive EWS cells have either wild type or transcriptional active P53, though mutated, and greatly benefit from MDM2 degradation. Due to the low rate of P53 inactivating mutations in EWS patients, these findings sustain CD99-targeting with specific MAbs either to directly kill EWS cells or to increase sensitivity to chemotherapy. By recruiting also RAS, CD99 delivers a signal which exceeds that of drugs designed exclusive to reactivate p53 functions, besides being easily druggable

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2017-01-02 | PXD005428 | Pride

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

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

| PRJNA528485 | ENA

Extracellular Vesicles in Luminal Fluid of the Ovine Uterus

2014-01-11 | GSE53974 | GEO

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