Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts.
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Date
2018-03-02ICR Author
Author
Legrand, AJ
Poletto, M
Pankova, D
Clementi, E
Moore, J
Castro-Giner, F
Ryan, AJ
O'Neill, E
Markkanen, E
Dianov, GL
Type
Journal Article
Metadata
Show full item recordAbstract
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 pro-inflammatory 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.
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Research team
Cell Death and Immunity
Language
eng
Date accepted
2018-01-30
License start date
2018-03
Citation
Oncotarget, 2018, 9 (17), pp. 13666 - 13681
Publisher
Impact Journals, LLC