Stress granules confer an early vulnerability in KRAS-driven pancreatic tumorigenesis.

Authors

Matias Estaras, Emma Cosialls, Gareth Pollin, Anass Berkachi, Noriyuki Nishiwaki, Gerardo Blanco, Miguel Fernandez-Bermejo, Antonio Gonzalez, Anil K Rustgi, Gwen Lomberk, Raul Urrutia, Patricia Santofimia-Castaño, Juan Iovanna

Published in

Cell reports. Volume 45. Issue 8. Pages 117829. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is initiated by activating KRAS mutations, yet most pancreatic cells fail to survive the induced oncogenic stress. How a subset adapts to and initiates malignant transformation remains unclear. Here, we show that stress granules (SGs) formation is a key adaptive mechanism enabling these cells to tolerate oncogenic KRAS signaling. Although we determine that SGs are a generic response in stressed acinar cells, they are required for KRAS-mutant cells to progress to the preneoplastic stage. SGs blocking prevents KRAS-driven acinar-to-ductal metaplasia ex vivo and suppresses preneoplastic lesion formation in vivo. Importantly, SGs inhibition does not affect pancreatic damage during chronic pancreatitis, supporting its safety for selectively targeting KRAS-mutant cells. Finally, SGs are detected in pancreatic tissue from patients with chronic pancreatitis, confirming clinical relevance. Together, these findings identify SGs as a stress adaptation mechanism enabling tumor initiation and highlight them as a target for cancer interception in KRAS-driven PDACs.

PMID:
42574223
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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