Expression of FUS-CHOP fusion protein in immortalized/transformed human mesenchymal stem cells drives mixoid liposarcoma formation

Authors

  • Rene Rodriguez,

    Corresponding author
    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
    • Correspondence: Pablo Menendez, Ph.D., Josep Carreras Leukemia Research Institute. Facultat de Medicina. University of Barcelona. Carrer de Casanova 143, 08036 Barcelona, Spain. Telephone: +34 655010572; Fax: +34 934651472; e-mail: pmenendez@carrerasresearch.org; or Rene Rodriguez, Ph.D., Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Laboratorio 2 ORL-IUOPA, C/Celestino Villamil s/n, 33006 Oviedo, Spain. Telephone: +34-985-10-80-00, ext. 38524; Fax: +34-985-10-80-15; e-mail: renerg@ficyt.es

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  • Juan Tornin,

    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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  • Carlos Suarez,

    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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  • Aurora Astudillo,

    1. Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain
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  • Ruth Rubio,

    1. GENYO. Centre for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Goverment, Granada, Spain
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  • Carole Yauk,

    1. Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Ottawa, Ontario, Canada
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  • Andrew Williams,

    1. Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Ottawa, Ontario, Canada
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  • Michael Rosu-Myles,

    1. Health Canada Centre for Biologics Research, Biologics and Genetic Therapies Directorate, Ottawa, Ontario, Canada
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  • Juan M. Funes,

    1. UCL Cancer Institute, University College London, London, United Kingdom
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  • Chris Boshoff,

    1. UCL Cancer Institute, University College London, London, United Kingdom
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  • Pablo Menendez

    Corresponding author
    1. GENYO. Centre for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Goverment, Granada, Spain
    2. Josep Carreras Leukemia Research Institute-Cell Therapy Program, University of Barcelona, Barcelona, Spain
    3. Institució Catalana de Reserca i Estudis Avançats (ICREA), Barcelona, Spain
    • Correspondence: Pablo Menendez, Ph.D., Josep Carreras Leukemia Research Institute. Facultat de Medicina. University of Barcelona. Carrer de Casanova 143, 08036 Barcelona, Spain. Telephone: +34 655010572; Fax: +34 934651472; e-mail: pmenendez@carrerasresearch.org; or Rene Rodriguez, Ph.D., Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Laboratorio 2 ORL-IUOPA, C/Celestino Villamil s/n, 33006 Oviedo, Spain. Telephone: +34-985-10-80-00, ext. 38524; Fax: +34-985-10-80-15; e-mail: renerg@ficyt.es

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  • Author contributions: J.T. and R.Ru.: performed experiments; C.S., A.A., C.Y., and A.W.: analyzed data and interpreted the results; J.M.F. and C.B.: provided key biological material; P.M.: conceived the study, analyzed the data, interpreted the results, wrote the paper, and financially supported the study; R.Ro.: conceived the study, designed the study, performed experiments, analyzed the data, interpreted the results, wrote the paper, and financially supported the study; M.R.-M.: analyzed data and interpreted the results and financially supported the study. P.M. and R.Ro. share senior authorship.

Abstract

Increasing evidence supports that mesenchymal stromal/stem cells (MSCs) may represent the target cell for sarcoma development. Although different sarcomas have been modeled in mice upon expression of fusion oncogenes in MSCs, sarcomagenesis has not been successfully modeled in human MSCs (hMSCs). We report that FUS-CHOP, a hallmark fusion gene in mixoid liposarcoma (MLS), has an instructive role in lineage commitment, and its expression in hMSC sequentially immortalized/transformed with up to five oncogenic hits (p53 and Rb deficiency, hTERT over-expression, c-myc stabilization, and H-RASv12 mutation) drives the formation of serially transplantable MLS. This is the first model of sarcoma based on the expression of a sarcoma-associated fusion protein in hMSC, and allowed us to unravel the differentiation processes and signaling pathways altered in the MLS-initiating cells. This study will contribute to test novel therapeutic approaches and constitutes a proof-of-concept to use hMSCs as target cell for modeling other fusion gene-associated human sarcomas. Stem Cells 2013;31:2061–2072

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