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

Legrand AJ., Poletto M., Pankova D., Clementi E., Moore J., Castro-Giner F., Ryan AJ., O'Neill E., Markkanen E., Dianov GL.

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.

DOI

10.18632/oncotarget.24446

Type

Journal article

Journal

Oncotarget

Publication Date

02/03/2018

Volume

9

Pages

13666 - 13681

Keywords

base excision repair, cancer-associated fibroblasts, midostaurin, tumour microenvironment, tumour stroma

Permalink Original publication