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

Sunita Shankar, Jean Ching-Yi Tien, Ronald F. Siebenaler, Seema Chugh, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Xiao-Ming Wang, Ingrid J. Apel, Jessica Waninger, Sanjana Eyunni, Alice Xu, Malay Mody, Andrew Goodrum, Yuping Zhang, John J. Tesmer, Rahul Mannan, Xuhong Cao, Pankaj Vats, Sethuramasundaram Pitchiaya, Stephanie J. Ellison, Jiaqi Shi, Chandan Kumar-Sinha, Howard C. Crawford and Arul M. Chinnaiyan ()
Additional contact information
Sunita Shankar: University of Michigan
Jean Ching-Yi Tien: University of Michigan
Ronald F. Siebenaler: University of Michigan
Seema Chugh: University of Michigan
Vijaya L. Dommeti: University of Michigan
Sylvia Zelenka-Wang: University of Michigan
Xiao-Ming Wang: University of Michigan
Ingrid J. Apel: University of Michigan
Jessica Waninger: University of Michigan
Sanjana Eyunni: University of Michigan
Alice Xu: University of Michigan
Malay Mody: University of Michigan
Andrew Goodrum: University of Michigan
Yuping Zhang: University of Michigan
John J. Tesmer: Purdue University
Rahul Mannan: University of Michigan
Xuhong Cao: University of Michigan
Pankaj Vats: University of Michigan
Sethuramasundaram Pitchiaya: University of Michigan
Stephanie J. Ellison: University of Michigan
Jiaqi Shi: University of Michigan
Chandan Kumar-Sinha: University of Michigan
Howard C. Crawford: University of Michigan
Arul M. Chinnaiyan: University of Michigan

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16309-2

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