Abstract
Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts and that the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increased transcription- and replication-dependent genomic instability, but also disrupted transcription reprogramming. Unexpectedly, ATR inhibition elevated R-loop–associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppressed R-loops and antagonized repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduced tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity.
Authors
Parasvi S. Patel, Jacob P. Matson, Xiaojuan Ran, Marcello Stanzione, Ajinkya S. Kawale, Mingchao Wang, Sneha Saxena, Conrad Sander, Jacquelyn Curtis, Jessica L. Hopkins, Edmond Wong, Ryan B. Corcoran, Daniel A. Haber, Nicholas J. Dyson, Shyamala Maheswaran, Lee Zou
Figure 2
ATR is required for efficient EMT.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)