CD99 Modulates the Proteomic Landscape of Ewing Sarcoma Cells and Related Extracellular Vesicles

Author:

De Feo Alessandra1ORCID,Manfredi Marcello2ORCID,Mancarella Caterina1ORCID,Maqueda Joaquín J.1ORCID,De Giorgis Veronica2,Pignochino Ymera34ORCID,Sciandra Marika1,Cristalli Camilla1ORCID,Donadelli Massimo5ORCID,Scotlandi Katia1ORCID

Affiliation:

1. Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy

2. Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy

3. Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy

4. Sarcoma Unit, Candiolo Cancer Institute, FPO-IRCCS, 10060 Turin, Italy

5. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy

Abstract

Ewing sarcoma (EWS) is an aggressive pediatric bone tumor characterized by unmet clinical needs and an incompletely understood epigenetic heterogeneity. Here, we considered CD99, a major surface molecule hallmark of EWS malignancy. Fluctuations in CD99 expression strongly impair cell dissemination, differentiation, and death. CD99 is also loaded within extracellular vesicles (EVs), and the delivery of CD99-positive or CD99-negative EVs dynamically exerts oncogenic or oncosuppressive functions to recipient cells, respectively. We undertook mass spectrometry and functional annotation analysis to investigate the consequences of CD99 silencing on the proteomic landscape of EWS cells and related EVs. Our data demonstrate that (i) the decrease in CD99 leads to major changes in the proteomic profile of EWS cells and EVs; (ii) intracellular and extracellular compartments display two distinct signatures of differentially expressed proteins; (iii) proteomic changes converge to the modulation of cell migration and immune-modulation biological processes; and (iv) CD99-silenced cells and related EVs are characterized by a migration-suppressive, pro-immunostimulatory proteomic profile. Overall, our data provide a novel source of CD99-associated protein biomarkers to be considered for further validation as mediators of EWS malignancy and as EWS disease liquid biopsy markers.

Funder

Fondazione AIRC per la ricerca sul cancro ETS

Publisher

MDPI AG

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