PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets
Gizaw, N. Y., Kallio, P., Punger, T., Gucciardo, E., Haglund, C., Böhling, T., Lehti, K., Sampo, M., Alitalo, K., & Kivelä, R. (2022). PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets. Proceedings of the National Academy of Sciences of the United States of America, 119(49), Article e2116220119. https://doi.org/10.1073/pnas.2116220119
Authors
Date
2022Copyright
© 2022 the Author(s). Published by PNAS.
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.
...
Publisher
National Academy of SciencesISSN Search the Publication Forum
0027-8424Keywords
Publication in research information system
https://converis.jyu.fi/converis/portal/detail/Publication/164368391
Metadata
Show full item recordCollections
- Liikuntatieteiden tiedekunta [3077]
Additional information about funding
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). ...License
Related items
Showing items with similar title or keywords.
-
Towards therapeutic gene delivery to human cancer cells : targeting and entry of baculovirus
Mäkelä, Anna (University of Jyväskylä, 2008)Geeniterapia on yksi tulevaisuuden hoitomuodoista taistelussa syöpää vastaan. Virukset ovat evoluution myötä kehittyneet tehokkaiksi geeninsiirtäjiksi ja ovat nykyään käytetyimpiä geeninsiirtovektoreita. Yksi geenihoitojen ... -
Validation of the breast cancer Analysis Protocol Packages (APPs) for the determination of estrogen and progesterone receptors (ER, PR), human epidermal growth factor recep- tor 2 (HER2) and proliferation index (Ki67) in breast cancer
Heikinmäki, Nella (2022)Rintasyöpä on naisten yleisin syöpä maailmassa. Sillä on merkittävä vaikutus kansanterveyteen sekä yhteiskuntaan ja tämän vuoksi sitä on tutkittu laajasti jo pitkään. Tämän opinnäytetyön tarkoituksena on validoida kaupallisen ... -
Assessment of targeted therapy opportunities in sinonasal cancers using patient-derived functional tumor models
Lehtinen, Noora; Suhonen, Janne; Rice, Kiesha; Välimäki, Eetu; Toriseva, Mervi; Routila, Johannes; Halme, Perttu; Rahi, Melissa; Irjala, Heikki; Leivo, Ilmo; Kallajoki, Markku; Nees, Matthias; Kuopio, Teijo; Ventelä, Sami; Rantala, Juha K. (Neoplasia Press, 2024)Malignant tumors derived from the epithelium lining the nasal cavity region are termed sinonasal cancers, a highly heterogeneous group of rare tumors accounting for 3 – 5 % of all head and neck cancers. Progress with ... -
Exercise Medicine for Cancer Cachexia : Targeted Exercise to Counteract Mechanisms and Treatment Side Effects
Mavropalias, Georgios; Sim, Marc; Taaffe, Dennis, R.; Galvão, Daniel A.; Spry, Nigel; Kraemer, William, J.; Häkkinen, Keijo; Newton, Robert, U. (Springer Science and Business Media LLC, 2022)Purpose -- Cancer-induced muscle wasting (i.e., cancer cachexia, CC) is a common and devastating syndrome that results in the death of more than 1 in 5 patients. Although primarily a result of elevated inflammation, there ... -
Ligand Ratio Plays a Critical Role in the Design of Optimal Multifunctional Gold Nanoclusters for Targeted Gastric Cancer Therapy
Matus, María Francisca; Malola, Sami; Häkkinen, Hannu (American Chemical Society (ACS), 2021)Nanodrug delivery systems (NDDSs) based on water-soluble and atomically precise gold nanoclusters (AuNCs) are under the spotlight due to their great potential in cancer theranostics. Gastric cancer (GC) is one of the most ...