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

    Research output: Contribution to journalArticlepeer-review

    12 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)13666-13681
    Number of pages16
    Issue number17
    Publication statusPublished - 2 Mar 2018


    • Base excision repair
    • Cancer-associated fibroblasts
    • Midostaurin
    • Tumour microenvironment
    • Tumour stroma


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