PROX1 transcription factor regulates rhabdomyosarcoma growth, myogenic properties and therapeutic targets
CLINICAL CANCER RESEARCH(2022)
Abstract
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, novel RMS therapies are urgently needed. Here we show that the 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 altered the RD (ERMS) 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, inhibition of either alone did not mimic the effects of PROX1 silencing, whereas a pan-FGFR inhibitor ablated RMS cell proliferation and decreased tumor xenograft growth. Our findings uncover the critical role of PROX1 in RMS and offer new insights to the mechanisms that regulate RMS development and growth. As FGFR inhibitors have already been tested in unrelated clinical trials, our findings provide a new promising option for RMS treatment. Citation Format: Nebeyu Y. Gizaw, Pauliina Kallio, Erika Gucciardo, Caj Haglund, Tom Bohling, Kaisa Lehti, Mika Sampo, Kari Alitalo, Riikka Kivela. PROX1 transcription factor regulates rhabdomyosarcoma growth, myogenic properties and therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A026.
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