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.

Original languageEnglish
Article numbere2116220119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number49
Number of pages10
ISSN0027-8424
DOIs
Publication statusPublished - 6 Dec 2022
MoE publication typeA1 Journal article-refereed

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We would like to thank Dr. Tuomas Tammela and Dr. Monika Ehnmann for providing RMS cell lines and Dr. Jenny Högström for discussions and comments during the project. Kirsi Mattinen, Jefim Brodkin, Maxime Laird, Manon Gruchet, Ilse Paetau, Tanja Laakkonen, and Tapio Tainola are acknowledged for their excellent technical help. We also thank the Laboratory Animal Center at the University of Helsinki for expert animal care, the Biomedicum Imaging Unit for microscope support, the Biomedicum Functional Genomics Unit for the RNAseq experiments and the FIMM Technology Centre High Throughput Biomedicine for the drug sensitivity and resistance testing. Our first findings on PROX1 involvement in RMS and analyses presented in this study were made in the Translational Cancer Biology Program, University of Helsinki and Wihuri Research Institute. The work was funded by the Cancer Foundation Finland sr., Barncancerfonden, the Academy of Finland (grants 297245, 320185, 292816, 273817, and 307366), the Sigrid Jusélius Foundation, Children’s Cancer Foundation Väre, the Doctoral School of Biomedicine, iCAN Digital Precision Cancer Medicine Flagship, K. Albin Johanssons stiftelse sr., and The Hospital District of Helsinki, Uusimaa Research Grants (THY2019202 and TYH202102).

Funding Information:
We would like to thank Dr. Tuomas Tammela and Dr. Monika Ehnmann for providing RMS cell lines and Dr. Jenny Högström for discussions and comments during the project. Kirsi Mattinen, Jefim Brodkin, Maxime Laird, Manon Gruchet, Ilse Paetau, Tanja Laakkonen, and Tapio Tainola are acknowledged for their excellent technical help. We also thank the Laboratory Animal Center at the University of Helsinki for expert animal care, the Biomedicum Imaging Unit for microscope support, the Biomedicum Functional Genomics Unit for the RNAseq experiments and the FIMM Technology Centre High Throughput Biomedicine for the drug sensitivity and resistance testing. Our first findings on PROX1 involvement in RMS and analyses presented in this study were made in the Translational Cancer Biology Program, University of Helsinki and Wihuri Research Institute. The work was funded by the Cancer Foundation Finland sr., Barncancerfonden, the Academy of Finland (grants 297245, 320185, 292816, 273817, and 307366), the Sigrid Jusélius Foundation, Children’s Cancer Foundation Väre, the Doctoral School of Biomedicine, iCAN Digital Precision Cancer Medicine Flagship, K. Albin Johanssons stiftelse sr., and The Hospital District of Helsinki, Uusimaa Research Grants (THY2019202 and TYH202102).

Publisher Copyright:
Copyright © 2022 the Author(s).

Fields of Science

  • cancer
  • FGFR
  • myogenesis
  • PROX1
  • sarcoma
  • 3122 Cancers
  • 3111 Biomedicine

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