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

Abstract

AbstractOver 90% of pancreatic ductal adenocarcinoma (PDAC) tumors harbor mutations inKRAS, 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 causes an accumulation of mRNA, which 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 and PI3K signaling. Targeted transcriptomic analysis suggests that KGs are enriched for transcripts targeted by misregulated miRNAs, leading to decreased mRNA turnover and increased translation of pro-tumor transcripts. Usingin vivoandin vitromodels, we find that genetic ablation of KGs leads to delayed tumorigenesis, reduced angiogenesis, and decreased innervation. Our findings reveal an essential and therapeutically targetable role for altered post-transcriptional regulation in PDAC tumorigenesis.