Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts
Metrics: PDF 640 views | HTML 1709 views | ?
Arnaud J. Legrand1,*, Mattia Poletto1,*, Daniela Pankova1, Elena Clementi2, John Moore1, Francesc Castro-Giner3, Anderson J. Ryan1, Eric O’Neill1, Enni Markkanen2,# and Grigory L. Dianov1,4,5,#
1CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
2Institute of Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, Zürich 8057, Switzerland
3Functional Genomics Center Zürich, University of Zürich, Zürich 8057, Switzerland
4Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk 630090, Russian Federation
5Novosibirsk State University, Novosibirsk 630090, Russian Federation
Grigory L. Dianov, email: email@example.com
Enni Markkanen, email: firstname.lastname@example.org
Keywords: tumour microenvironment; cancer-associated fibroblasts; base excision repair; tumour stroma; midostaurin
Received: October 11, 2017 Accepted: January 30, 2018 Published: February 07, 2018
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.