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

Journal article

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.

Authors: Legrand, A; Poletto, M; Pankova, D; Clementi, E; Moore, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Impact Journals
• Journal: Oncotarget
• Volume: 9
• Issue: 17
• Pages: 13666-13681
• Publication date: 2018-02-07
• Acceptance date: 2018-01-30
• DOI: 10.18632/oncotarget.24446
• ISSN: 1949-2553
• Pmid: 29568385
• Language: English
• Keywords: cancer-associated fibroblasts; tumour microenvironment; midostaurin; tumour stroma; base excision repair