PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets

Abstract

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft-tissue cancer with features of skeletal muscle. Because of poor survival of RMS patients and severe long-term side effects of RMS therapies, alternative RMS therapies are urgently needed. Here we show that the prospero-related homeobox 1 (PROX1) transcription factor is highly expressed in RMS tumors regardless of their cell type of origin. We demonstrate that PROX1 is needed for RMS cell clonogenicity, growth and tumor formation. PROX1 gene silencing repressed several myogenic and tumorigenic transcripts and transformed the RD cell transcriptome to resemble that of benign mesenchymal stem cells. Importantly, we found that fibroblast growth factor receptors (FGFR) mediated the growth effects of PROX1 in RMS. Because of receptor cross-compensation, paralog-specific FGFR inhibition did not mimic the effects of PROX1 silencing, whereas a pan-FGFR inhibitor ablated RMS cell proliferation and induced apoptosis. Our findings uncover the critical role of PROX1 in RMS and offer insights into the mechanisms that regulate RMS development and growth. As FGFR inhibitors have already been tested in clinical phase I/II trials in other cancer types, our findings provide an alternative option for RMS treatment.

The Comparison of Commercial Serum-Free Media for Hanwoo Satellite Cell Proliferation and the Role of Fibroblast Growth Factor 2

“…Previous studies showed that PD173074 inhibits the growth of human RD cells isolated from human muscle tissue ( Gizaw et al, 2022 ), and downregulates FGFR1-mediated p38 phosphorylation induced by Lycium barbarum extract in C2C12 cells ( Meng et al, 2023 ). Similar to these studies, our results indicated that PD173074 inhibits HWSC proliferation via FGFR1-dependent signaling, especially the FRS2/Raf1/ERK pathway ( Fig.…”

“…Previous studies showed that PD173074 inhibits the growth of human RD cells isolated from human muscle tissue (Gizaw et al, 2022), and downregulates FGFR1-mediated p38 phosphorylation induced by Lycium barbarum extract in C2C12 cells (Meng et al, 2023).…”