An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development

Sunita Shankar,Yuping Zhang,Xiaoming Wang ,Ronald F Siebenaler,John J.g Tesmer ,Alice Xu,Stephanie J Ellison,Sylvia Zelenka-Wang,Pankaj Vats,Ingrid J Apel,Xuhong Cao,Jiaqi Shi,Seema Chugh,Rahul Mannan,Andrew Goodrum,Chandan Kumar‐Sinha ,Malay Mody,Jean C Tien ,Vijaya L Dommeti,Sanjana Eyunni,Jessica Waninger,Sethuramasundaram Pitchiaya,Howard C Crawford

doi:10.1038/s41467-020-16309-2

Abstract

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53. In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRASG12C-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.

Highlights

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function
We identified a direct interaction between KRAS and Argonaute 2 (AGO2), independent of KRAS mutation status[11], which was required for oncogenic KRAS-driven cellular transformation
Crossing KRASG12D mice with animals harboring Cre recombinase knocked into the pancreas-specific promoter, p48 (p48Cre), yields KRASG12D; p48Cre mice that develop pancreatic intraepithelial neoplasia (PanINs) precursor lesions beginning around 8 weeks[4]

Summary

Introduction

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. In a mouse model of mutant KRASdriven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression. Engineered mouse models (GEMMs) of pancreatic cancer were developed by expression of a single oncogenic KRASG12D allele in the mouse exocrine pancreas. In this model, pre-invasive pancreatic intraepithelial (PanINs) lesions progress to pancreatic adenocarcinoma (PDAC) reflective of the human disease[4]. Disruption of the oncogenic KRASAGO2 association may, represent a point of therapeutic intervention to prevent pancreatic cancer progression

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Conclusion