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Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4

  • Author Footnotes
    5 These authors contributed equally to this work.
    Anna Aronovich
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Division of Dermatology, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Lilach Moyal
    Correspondence
    Correspondence: Lilach Moyal, Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel.
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Division of Dermatology, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for articles by this author
  • Batia Gorovitz
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Iris Amitay-Laish
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Division of Dermatology, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Hadas Prag Naveh
    Affiliations
    Division of Dermatology, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Yaara Forer
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Lea Maron
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Jamal Knaneh
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Dean Ad-El
    Affiliations
    Department of Plastic and Reconstructive Surgery, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Dafna Yaacobi
    Affiliations
    Department of Plastic and Reconstructive Surgery, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Eric Barel
    Affiliations
    Department of Plastic and Reconstructive Surgery, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Neta Erez
    Affiliations
    Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Emmilia Hodak
    Affiliations
    Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Division of Dermatology, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for articles by this author
  • Author Footnotes
    5 These authors contributed equally to this work.
Published:August 11, 2020DOI:https://doi.org/10.1016/j.jid.2020.06.034
      Cancer cells are known to reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) to act as tumor supporters. The presence and role of CAFs in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, are unknown. This study sought to characterize CAFs in MF and their cross talk with the lymphoma cells using primary fibroblast cultures from punch biopsies of patients with early-stage MF and healthy subjects. MF cultures yielded significantly increased levels of FAPα, a CAF marker, and CAF-associated genes and proteins: CXCL12 (ligand of CXCR4 expressed on MF cells), collagen XI, and matrix metalloproteinase 2. Cultured MF fibroblasts showed greater proliferation than normal fibroblasts in ex vivo experiments. A coculture with MyLa cells (MF cell line) increased normal fibroblast growth, reduced the sensitivity of MyLa cells to doxorubicin, and enhanced their migration. Inhibiting the CXCL12/CXCR4 axis increased doxorubicin-induced apoptosis of MyLa cells and reduced MyLa cell motility. Our data suggest that the fibroblasts in MF lesions are more proliferative than fibroblasts in normal skin and that CAFs protect MF cells from doxorubicin-induced cell death and increase their migration through the secretion of CXCL12. Reversing the CAF-mediated tumor microenvironment in MF may improve the efficiency of anticancer therapy.

      Abbreviations:

      CAF (cancer-associated fibroblast), Doxo (doxorubicin), ECM (extracellular matrix), MF (mycosis fungoides), MF-F (fibroblast from patient with MF), MMP (matrix metalloproteinase), N-F (fibroblast from control subject), PBMC (peripheral blood mononuclear cell), XTT (Cell Proliferation Kit II)
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