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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.
Highlights
Cancer cells heavily depend on a microenvironment that sustains their metabolism and proliferation, promotes their survival and ensures their ability to migrate and invade the surrounding tissue [1]
Can unrepaired DNA strand breaks act as a trigger for trans-differentiation of normal fibroblasts? Tumours generally develop within a pro-inflammatory microenvironment, where a sustained release of proinflammatory and pro-fibrotic cytokines (e.g. TGFβ) by a variety of cell types accompanied by an increase in reactive oxygen species (ROS) production promote the generation of CAFs5
We tested whether prolonged exposure of fibroblasts to either ROS or TGFβ could lead to an accumulation of unrepaired DNA damage
Summary
Cancer cells heavily depend on a microenvironment that sustains their metabolism and proliferation, promotes their survival and ensures their ability to migrate and invade the surrounding tissue [1]. Www.impactjournals.com/oncotarget and/or reactive oxygen species (ROS) [5, 6]. It remains unclear how TGFβ or ROS may condition fibroblasts and drive their change into CAFs on a molecular basis. ROS can target DNA and induce a wide range of oxidative DNA lesions [7], which are usually eliminated by the base excision repair (BER) pathway [8]. We have recently demonstrated that accumulation of unrepaired SSBs in normal human fibroblasts leads to a cellular response whose proteomic profile is reminiscent of that observed in CAFs and cancer cells [10].
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