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Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinoma

E. Mammadova-Bach, T. Rupp, C. Spenlé, I. Jivkov, P. Shankaranarayanan, A. Klein, L. Pisarsky, A. Méchine-Neuville, G. Cremel, M. Kedinger, O. De Wever, N. Ambartsumian, S. Robine, E. Pencreach, D. Guenot, View ORCID ProfileJ.G. Goetz, P. Simon-Assmann, G. Orend, O. Lefebvre
doi: https://doi.org/10.1101/099465
E. Mammadova-Bach
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
5present address, Inserm UMR-S 949, Etablissement Français du Sang-Alsace, Strasbourg, F-67065, France.
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T. Rupp
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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C. Spenlé
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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I. Jivkov
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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P. Shankaranarayanan
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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A. Klein
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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L. Pisarsky
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
6present Adress, Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
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A. Méchine-Neuville
7Department of Anatomy and Pathology, CHRU Hautepierre, Strasbourg, F-67200, France.
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G. Cremel
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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M. Kedinger
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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O. De Wever
8laboratory of Experimental Cancer Research, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Ghent, 9000, Belgium.
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N. Ambartsumian
9Institut for Cancer Biology, Copenhagen, DK-2100, Denmark.
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S. Robine
10Institut Curie, Paris, F-75248, France.
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E. Pencreach
11EA 3430, Université de Strasbourg, Strasbourg, F-67000, France.
12Plateforme de Génétique Moléculaire des Cancers, Hôpitaux Universitaires de Strasbourg, Strasbourg, F-67098, France.
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D. Guenot
11EA 3430, Université de Strasbourg, Strasbourg, F-67000, France.
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J.G. Goetz
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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  • ORCID record for J.G. Goetz
  • For correspondence: jacky.goetz@inserm.fr gertraud.orend@inserm.fr olivier.lefebvre@inserm.fr
P. Simon-Assmann
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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G. Orend
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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  • For correspondence: jacky.goetz@inserm.fr gertraud.orend@inserm.fr olivier.lefebvre@inserm.fr
O. Lefebvre
1Inserm U1109, MN3T, Strasbourg, F-67200, France.
2Université de Strasbourg, Strasbourg, F-67000, France.
3LabEx Medalis, Université de Strasbourg, Strasbourg, F-67000, France.
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France.
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  • For correspondence: jacky.goetz@inserm.fr gertraud.orend@inserm.fr olivier.lefebvre@inserm.fr
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Summary

Tumor stroma remodeling is a key feature of malignant tumors and can promote cancer progression. Laminins are major constituents of basement membranes that physically separate the epithelium from the underlying stroma. By employing mouse models expressing high and low levels of the laminin α1 chain (LMα1), we highlighted its implication in a tumorstroma crosstalk, thus leading to increased colon tumor incidence, angiogenesis and tumor growth. The underlying mechanism involves attraction of carcinoma-associated fibroblasts by LMα1, VEGFA expression triggered by the complex integrin α2β1-CXCR4 and binding of VEGFA to LM-111, which in turn promotes angiogenesis, tumor cell survival and proliferation. A gene signature comprising LAMA1, ITGB1, ITGA2, CXCR4 and VEGFA has negative predictive value in colon cancer. Together, this information opens novel opportunities for diagnosis and anti-cancer targeting.

  • Abbreviations

    BM
    basement membrane
    ECM
    extracellular matrix
    LM
    laminin
    vLMα1
    villin-LMα1 transgenic mice
    CAFs
    cancer-associated fibroblasts
    IF
    immunofluorescence
    VEGF
    vascular endothelial growth factor.
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted January 10, 2017.
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    Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinoma
    E. Mammadova-Bach, T. Rupp, C. Spenlé, I. Jivkov, P. Shankaranarayanan, A. Klein, L. Pisarsky, A. Méchine-Neuville, G. Cremel, M. Kedinger, O. De Wever, N. Ambartsumian, S. Robine, E. Pencreach, D. Guenot, J.G. Goetz, P. Simon-Assmann, G. Orend, O. Lefebvre
    bioRxiv 099465; doi: https://doi.org/10.1101/099465
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    Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinoma
    E. Mammadova-Bach, T. Rupp, C. Spenlé, I. Jivkov, P. Shankaranarayanan, A. Klein, L. Pisarsky, A. Méchine-Neuville, G. Cremel, M. Kedinger, O. De Wever, N. Ambartsumian, S. Robine, E. Pencreach, D. Guenot, J.G. Goetz, P. Simon-Assmann, G. Orend, O. Lefebvre
    bioRxiv 099465; doi: https://doi.org/10.1101/099465

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