GPX1 expression promotes stemness and aggressiveness in myxoid liposarcomas.

The sarcomagenic process initiates when mesenchymal stromal/stem cells (MSCs) or MSC-derived cells undergo tumoral transformation. Besides, sarcoma evolution is partly driven by the emergence of subpopulations of cancer stem cells (CSCs), which are strongly associated with more aggressive behaviors. Therefore, the characterization of CSC will contribute to the development of more effective therapies against sarcomas. Here, we compared the proteomes of adherent and CSC-enriched tumorsphere cultures in a tumor progression model of myxoid liposarcoma composed of three cell lines showing increasing aggressiveness after being serially transplanted in mice. We found that the expression of the antioxidant enzyme GPX1 increased constantly during the CSC-enrichment process in this model and other sarcoma lines. Depletion of GPX1 resulted in decreased proliferation and tumorsphere-forming potential and dramatically reduced tumor-formation ability in vivo. Conversely, GPX1 overexpression resulted in increased proliferation and tumorsphere formation. According to these findings, GPX1 expression in sarcoma patients was associated with aggressive phenotypes and worse prognosis. A proteomic analysis revealed that these effects were associated with the downregulation of interferon-mediated response, the IL6/JAK/STAT3 axis and the NFκB-mediated signaling in GPX1-silenced cells. Overall, these results suggest that GPX1 expression may serve as a functional marker of aggressive CSC subpopulations in sarcomas.