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