Oncogenic KRAS promotes pancreatic ductal adenocarcinoma (PDAC) through post-transcriptionally regulated KRAS-induced granules (KGs) [miRNA-seq]

ABSTRACT: Over 90% of pancreatic ductal adenocarcinoma (PDAC) tumors harbor mutations in KRAS which promote many hallmark characteristics of cancer. How a single driver mutation causes the malignant properties observed in PDAC is poorly understood. We discovered that oncogenic KRAS suppresses miRNA biogenesis and function, thus increasing the stability and translation efficiency of miRNA targets. Defective miRNA function causes an accumulation of mRNA, and drives the localization of components of the mRNA degradation machinery into novel post-transcriptional condensates termed KRAS-induced granules (KGs). Mechanistically, we find that KG formation depends on the phosphorylation of Argonaute2 at tyrosine393 and requires EGFR, but not MEK or PI3K signaling. Using in vivo and in vitro models, we find that genetic ablation of KGs leads to decreased proliferation and migration, delayed tumorigenesis, and reduced tumor angiogenesis and innervation. Our findings reveal an essential and therapeutically targetable role for altered post-transcriptional regulation in PDAC tumorigenesis.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE239309 | GEO | 2026/08/17

REPOSITORIES: GEO