ATR senses stiff extracellular matrix to promote epithelial-to-mesenchymal transition and immune suppression.
basic_science · Level V
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- Record sourced from PubMed, PMID 42412560.
- Also identified by DOI 10.1172/JCI192285.
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Abstract
Our research uncovers a new role for ATR in responding to extracellular matrix (ECM) stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2 which promotes β-catenin nuclear translocation and EMT. ATM mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103+ dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal to epithelial transition to enhance anti-tumor immunity and mitigate metastases. Consistently, circulating HLA-DR+ dendritic cells were also enhanced following treatment with the ATR inhibitor, Berzosertib, in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR targeted therapy may be optimized by considering both DNA damage dependent and EMT inducing effects of ATR.