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

ABSTRACT: Over 90% of pancreatic ductal adenocarcinoma (PDAC) tumors harbor mutations in KRAS which promote many hallmark characteristics of cancer. The mechanisms by which a single driver mutation results in the malignant properties of PDAC remain poorly understood. Here, we find that oncogenic KRAS suppresses miRNA biogenesis and function, thus increasing the stability and translational efficiency of miRNA targets. Altered miRNA function leads to mRNA accumulation and drives the localization of miRNA machinery components into large and static cytoplasmic membraneless organelles, termed KRAS-induced granules (K-granules). Mechanistically, we find that K-granule formation depends on the phosphorylation of Argonaute-2 at tyrosine 393 and requires EGFR, but not MEK or PI3K signaling. Using in vivo and in vitro models, we find that disruption of K-granules 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

PROVIDER: GSE285095 | GEO | 2026/08/17

REPOSITORIES: GEO