Emerging roles of ATR beyond DNA damage repair: orchestrating transcriptional reprogramming during epithelial-to-mesenchymal transition
Aida Mestre-Farrera, Zhimin Hu, Jing Yang
Aida Mestre-Farrera, Zhimin Hu, Jing Yang
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Commentary

Emerging roles of ATR beyond DNA damage repair: orchestrating transcriptional reprogramming during epithelial-to-mesenchymal transition

Abstract

The ability of cancer cells to transition between epithelial and mesenchymal states, a process known as epithelial-to-mesenchymal transition (EMT), is a key driver of cancer metastasis and therapy resistance. While ataxia telangiectasia and Rad3-related (ATR) kinase was originally characterized as a responder to DNA damage and replication stress, recent discoveries implicate a critical role for ATR in EMT and metastasis. Two pivotal studies published in this issue of JCI provide key insights into how ATR intersects with EMT transcriptional reprogramming. Patel et al. demonstrated that ATR prevented R-loop accumulation at EMT-related gene loci, thereby facilitating the transcriptional reprogramming necessary for EMT as well as tumor growth and metastasis. Tu et al. further uncovered a role for ATR in ECM stiffness–induced EMT, which was associated with an immunosuppressive tumor microenvironment. Together, these studies highlight important therapeutic implications for ATR targeting in the context of metastasis and therapy resistance.

Authors

Aida Mestre-Farrera, Zhimin Hu, Jing Yang

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Figure 1

ATR integrates ECM mechanical input and transcriptional stress to regulate EMT plasticity.

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ATR integrates ECM mechanical input and transcriptional stress to regula...
(A) During EMT, epithelial cells lose polarity and acquire traits of mesenchymal cells that support tumor progression and metastasis, including enhanced motility, stem-like properties, and resistance to antitumor therapies. This gradual transition allows tumor cells to adapt to stressors and limitations of the tumor microenvironment. (B) Patel et al. (14) showed that during tumor development, tumor cells undergoing EMT experienced transcriptional stress and R-loop accumulation, which activated ATR. In parallel, Tu et al. (15) found that increasing ECM stiffness stabilized ATR via USP21-mediated deubiquitination, which further enhanced EMT transition. At high ECM stiffness, tumor cells transitioned toward a mesenchymal state, gained invasiveness, and promoted an immunosuppressive tumor microenvironment, characterized by increased PMN myeloid-derived suppressor cells (PMN-MDSCs) and Tregs and decreased CD103+ dendritic cells (DCs). DDR, DNA damage response. (C) Pharmacological inhibition of ATR in the work of Patel et al. and Tu et al. disrupted EMT-associated transcriptional programs and enhanced antitumor immunity, respectively. Collectively, these effects suppressed tumor progression and metastasis.