Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts

Arnaud J. Legrand, Mattia Poletto, Daniela Pankova, Elena Clementi, John Moore, Francesc Castro-Giner, Anderson J. Ryan, Eric O'Neill, Enni Markkanen, Grigory L. Dianov

    Результат исследования: Научные публикации в периодических изданияхстатья

    5 Цитирования (Scopus)

    Аннотация

    Cancer-associated fibroblasts (CAFs) are an emerging target for cancer therapy as they promote tumour growth and metastatic potential. However, CAF targeting is complicated by the lack of knowledge-based strategies aiming to selectively eliminate these cells. There is a growing body of evidence suggesting that a proinflammatory microenvironment (e.g. ROS and cytokines) promotes CAF formation during tumorigenesis, although the exact mechanisms involved remain unclear. In this study, we reveal that a prolonged pro-inflammatory stimulation causes a de facto deficiency in base excision repair, generating unrepaired DNA strand breaks and thereby triggering an ATF4-dependent reprogramming of normal fibroblasts into CAF-like cells. Based on the phenotype of in vitro-generated CAFs, we demonstrate that midostaurin, a clinically relevant compound, selectively eliminates CAF-like cells deficient in base excision repair and prevents their stimulatory role in cancer cell growth and migration.

    Язык оригиналаанглийский
    Страницы (с-по)13666-13681
    Число страниц16
    ЖурналOncotarget
    Том9
    Номер выпуска17
    DOI
    СостояниеОпубликовано - 2 мар 2018

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  • Цитировать

    Legrand, A. J., Poletto, M., Pankova, D., Clementi, E., Moore, J., Castro-Giner, F., Ryan, A. J., O'Neill, E., Markkanen, E., & Dianov, G. L. (2018). Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts. Oncotarget, 9(17), 13666-13681. https://doi.org/10.18632/oncotarget.24446