P-cadherin is a direct PAX3-FOXO1A target involved in alveolar rhabdomyosarcoma aggressiveness

Universités Montpellier 2 et 1, CRBM, CNRS, UMR 5237, Montpellier, France.
Oncogene (Impact Factor: 8.46). 06/2012; 32(15). DOI: 10.1038/onc.2012.217
Source: PubMed


Alveolar rhabdomyosarcoma (ARMS) is an aggressive childhood cancer of striated muscle characterized by the presence of the PAX3-FOXO1A or PAX7-FOXO1A chimeric oncogenic transcription factor. Identification of their targets is essential for understanding ARMS pathogenesis. To this aim, we analyzed transcriptomic data from rhabdomyosarcoma samples and found that P-cadherin expression is correlated with PAX3/7-FOXO1A presence. We then show that expression of a PAX3 dominant negative variant inhibits P-cadherin expression in ARMS cells. Using mouse models carrying modified Pax3 alleles, we demonstrate that P-cadherin is expressed in the dermomyotome and lies genetically downstream from the myogenic factor Pax3. Moreover, in vitro gel shift analysis and chromatin immunoprecipitation indicate that the P-cadherin gene is a direct transcriptional target for PAX3/7-FOXO1A. Finally, P-cadherin expression in normal myoblasts inhibits myogenesis and induces myoblast transformation, migration and invasion. Conversely, P-cadherin downregulation by small hairpin RNA decreases the transformation, migration and invasive potential of ARMS cells. P-cadherin also favors cadherin switching, which is a hallmark of metastatic progression, by controlling N- and M-cadherin expression and/or localization. Our findings demonstrate that P-cadherin is a direct PAX3-FOXO1A transcriptional target involved in ARMS aggressiveness. Therefore, P-cadherin emerges as a new and attractive target for therapeutic intervention in ARMS.Oncogene advance online publication, 18 June 2012; doi:10.1038/onc.2012.217.

Download full-text


Available from: Cecile Gauthier-Rouviere
  • Source
    • "RMS cell lines were all grown in either RPMI-1640 (RH28, JR, RH18, RD, CTR, BIRCH, TTC-516, and TTC-442) or DMEM medium (RD, RH30, RH4, RH5, RH41, and RH36) (Quality Biological) supplemented with 10% FBS (Hyclone), 2 mM L-glutamine (Quality Biological), and 1% penicillin/streptomycin (Quality Biological). All RMS cell lines were previously established [18], [19] and kind gifts from Dr. Timothy Triche (Children's Hospital of Los Angeles). Ba/F3 cells (RCB0805; Riken BRC) were cultured in RPMI-1640 medium supplemented with 10% FBS, 2 mM L-glutamine, 1% penicillin/streptomycin, and 10% of WEHI-3BD conditioned medium, which contains IL-3. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.
    Full-text · Article · Oct 2013 · PLoS ONE
  • Source
    • "The CDH3/P-cadherin gene has been identified as a direct transcriptional target of PAX3/7-FOXO1 [72,76,80]. P-cadherin expression in the C2C12 myoblast cell line inhibits myogenic differentiation and maintains a proliferative state through maintaining cyclin D1 expression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rhabdomyosarcoma is a soft tissue sarcoma arising from cells of a mesenchymal or skeletal muscle lineage. Alveolar rhabdomyosarcoma (ARMS) is more aggressive than the more common embryonal (ERMS) subtype. ARMS is more prone to metastasis and carries a poorer prognosis. In contrast to ERMS, the majority of ARMS tumors carry one of several characteristic chromosomal translocations, such as t(2;13)(q35;q14), which results in the expression of a PAX3-FOXO1 fusion transcription factor. In this review we discuss the genes that cooperate with PAX3-FOXO1, as well as the target genes of the fusion transcription factors that contribute to various aspects of ARMS tumorigenesis. The characterization of these pathways will lead to a better understanding of ARMS tumorigenesis and will allow the design of novel targeted therapies that will lead to better treatment for this aggressive pediatric tumor.
    Full-text · Article · Dec 2012 · Skeletal Muscle
  • [Show abstract] [Hide abstract]
    ABSTRACT: Loss of cadherin 1 (CDH1; also known as epithelial cadherin (E-cadherin)) is used for the diagnosis and prognosis of epithelial cancers. However, it should not be ignored that the superfamily of transmembrane cadherin proteins encompasses more than 100 members in humans, including other classical cadherins, numerous protocadherins and cadherin-related proteins. Elucidation of their roles in suppression versus initiation or progression of various tumour types is a young but fascinating field of molecular cancer research. These cadherins are very diverse in both structure and function, and their mutual interactions seem to influence biological responses in complex and versatile ways.
    No preview · Article · Jan 2014 · Nature Reviews Cancer
Show more