TrkC, a Novel Prognostic Marker, Induces and Maintains Cell Survival and Metastatic Dissemination of Ewing Sarcoma by Inhibiting EWSR1-FLI1 Degradation

Upregulation of EWSR1-FLI1 expression has been associated with invasiveness, induced cell survival, metastatic dissemination, and acquisition of self-renewal traits in Ewing sarcoma (ES). Although existing evidence implies that TrkC expression is linked to the pathogenesis of other cancer types, its role and the mechanism behind its correlation with EWSR1-FLI1 in the pathogenesis of ES remain unclear. In this study, we uncovered a novel physiological role of TrkC as a key regulator of EWSR1-FLI1 involved in the survival and metastatic dissemination of ES. TrkC was observed to be frequently overexpressed in human metastatic ES cells in vitro and in vivo, facilitating enhanced survival, tumorigenicity, and metastasis of ES cells. TrkC-mediated metastasis of ES cells was induced by the inhibition of the proteasomal degradation of EWSR1-FLI1 via the TrkC/EWSR1-FLI1 complex, which subsequently enabled the induction of the target proteins, EGR2 and NKX2.2. Moreover, TrkC significantly inhibited tumor suppressor activity of TGF-β through reduction of the mRNA expression of one of its receptors, TGFBR2 via TrkC-induced stabilization of EWSR1-FLI1. Furthermore, loss of TrkC expression inhibited tumor growth and metastasis in experimental mouse models. This study is the first to report the involvement and functional role of TrkC in the pathogenesis of ES, suggesting important implications for understanding the alterations of TrkC in Ewing tumors.