Elevated FN14 expression promotes proliferation, chemoresistance, and impairment of differentiation in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children and adolescents and is characterized by expression of myogenic regulatory factors without terminal differentiation. Treatment of RMS remains challenging, with nearly one-third of patients experiencing relapse due to chemotherapy resistance. However, the molecular mechanisms underlying RMS growth and chemoresistance remain poorly understood. Fibroblast growth factor-inducible 14 (FN14), a receptor for the TWEAK cytokine, has been implicated in tumor progression in several cancers, but its role in RMS is unknown. Here, we demonstrate that FN14 expression is highly upregulated in human RMS samples and in the RD and RH30 RMS cell lines. Silencing FN14 reduced proliferation and survival of RMS cells. In a xenograft model, inducible FN14 knockdown transiently delayed tumor growth, supporting a functional role for FN14 in RMS growth in vivo. FN14 expression was further increased in vincristine-resistant RD cells, and FN14 knockdown suppressed the proliferation and survival of these chemoresistant cells. Mechanistic studies performed primarily in RD cells showed that FN14 promotes ERK1/2 signaling. Consistent with this finding, pharmacological inhibition of ERK1/2 reduced RD cell proliferation and survival. Furthermore, both FN14 silencing and ERK1/2 inhibition decreased mitochondrial oxidative phosphorylation in RD cells. Finally, inhibition of either FN14 or ERK1/2 promoted myogenic differentiation in parental and vincristine-resistant RD cells. Collectively, our experiments support FN14 as an important regulator of proliferation, survival, chemoresistance, and differentiation in RMS and support further investigation of FN14-mediated signaling in RMS pathogenesis.