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Autocrine role for Gas6 with Tyro3 and Axl in leiomyosarcomas

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Abstract

Leiomyosarcoma (LMS) represent 15 % of adult sarcomas. The aim of this work was to identify novel altered pathways in LMS, which may be of therapeutic value for patients. Thirteen fresh frozen samples of soft tissue and visceral LMS were analyzed and compared with normal smooth muscle uterine tissue (NSM) for phosphoproteomic profile. Four proteins were found differentially expressed including Tyro3. The functional role of Tyro3 and its ligand Gas6 was investigated in two LMS cell lines, SK-LMS-1 and CNIO-AA. Four proteins and phosphoproteins were differentially expressed in LMS samples vs NSM: A loss of FAK Y397 phosphorylation was observed in all LMSs, while Tyro3, MSH2 and PKC theta were consistently overexpressed. Gas6, the major ligand of Tyro3, was expressed in 8 of the 13 LMS samples, and Gas6 expression highly correlated to Akt Y473 phosphorylation and to a lesser extent to Erk1/2 phosphorylation. SK-LMS-1 and CNIO-AA LMS expressed Tyro3, Axl and Gas6 at high level in CNIO-AA while at low levels in SK-LMS-1. Exposure of both cell lines to foretinib, a tyrosine kinase inhibitor of Met, Axl and Tyro3, reduced cell viability and induced caspase 3/7 activation. Transfection of CNIO-AA with small interfering RNA directed against Tyro3 and Axl genes induced a reduction of the expression of the specific proteins and, when combined, significantly reduced CNIO-AA cell viability. Leiomyosarcomas overexpress Tyro3. Gas6, a ligand of Tyro3, exerts an autocrine activities though Tyro3 and Axl in a subgroup of LMS.

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Acknowledgments

We thank Pharmamar for providing the CNIO-AA cell line (Dr M. Aracil). Foretinib was kindly provided by Glaxo Smith Kline (Dr T. Gilmer).

Grant support

HES received a grant from CONTICANET Network of Excellence FP6-018806. This work was supported in part by grants from Association pour la Recherche sur le Cancer, Ligue contre le Cancer (Comité de l’Ain et Comité du Rhône), the Breast Cancer Research Foundation, the DEVweCAN Labex Cancéropôle Lyon Auvergne Rhône Alpes and support from the French National Cancer Institute, through the NETSARC and RREPS grants and the LYRIC (INCA_4664) grant. The research leading to these results has received funding from the European Union Seventh Framework Programme—EuroSarc- (FP7/2007-2013) under grant agreement number 278742.

Conflict of interest statement

JYB received research support and honoraria not related to this work from Novartis, Roche, GSK, Pharmamar, MSD.

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Authors and Affiliations

  1. Pole des Sciences Cliniques & Centre de Recherche en Cancerologie de Lyon, INSERM UMR5286 Equipe 11, Centre Léon Bérard, Lyon, France

    Hiba el Sayadi, Daniel Pissaloux, Laurent Alberti, Severine Tabone-Eglinger, Christophe Caux & Jean-Yves Blay

  2. Service d’anatomie pathologique, Centre Léon Bérard, Lyon, France

    Dominique Ranchere, Anne Valérie Decouvelaere & Eric Tabone

  3. Département de Médecine Centre Léon Bérard, 28 rue Laënnec, 69373, Lyon cedex 08, France

    Isabelle Ray-Coquard, Jérome Fayette & Jean-Yves Blay

  4. Université Claude Bernard Lyon 1, Lyon, France

    Jean-Yves Blay

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  1. Hiba el Sayadi
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Correspondence to Jean-Yves Blay.

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H. el Sayadi and D. Pissaloux contributed equally to this work.

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el Sayadi, H., Pissaloux, D., Alberti, L. et al. Autocrine role for Gas6 with Tyro3 and Axl in leiomyosarcomas. Targ Oncol 8, 261–269 (2013). https://doi.org/10.1007/s11523-012-0249-2

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  • DOI: https://doi.org/10.1007/s11523-012-0249-2

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