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

Abstract

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: 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
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 17 Pg. 13666-13681 (Mar 02 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 29568385 (Publication Type: Journal Article)