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; Arul M Chinnaiyan

doi:10.1038/s41467-020-16309-2

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

Nat Commun. 2020 Jun 4;11(1):2817. doi: 10.1038/s41467-020-16309-2.

Authors

Sunita Shankar^#^{1

2}, Jean Ching-Yi Tien^#^{1

2}, Ronald F Siebenaler^#^{1

2}, Seema Chugh^#^{1

2}, Vijaya L Dommeti^{1

2}, Sylvia Zelenka-Wang^{1

2}, Xiao-Ming Wang^{1

2}, Ingrid J Apel^{1

2}, Jessica Waninger^{1

2}, Sanjana Eyunni^{1

2}, Alice Xu^{1

2}, Malay Mody^{1

2}, Andrew Goodrum^{1

2}, Yuping Zhang^{1

2}, John J Tesmer³, Rahul Mannan^{1

2}, Xuhong Cao^{1

2

4}, Pankaj Vats^{1

2}, Sethuramasundaram Pitchiaya^{1

2}, Stephanie J Ellison^{1

2}, Jiaqi Shi², Chandan Kumar-Sinha^{1

2}, Howard C Crawford^{5

6}, Arul M Chinnaiyan^{7

8

9

10

11}

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
² Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
⁴ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
⁵ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
⁶ Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
⁷ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA. arul@umich.edu.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA. arul@umich.edu.
⁹ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, 48109, USA. arul@umich.edu.
¹⁰ Department of Urology, University of Michigan, Ann Arbor, MI, 48109, USA. arul@umich.edu.
¹¹ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA. arul@umich.edu.

^# Contributed equally.

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 AGO2^Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRAS^G12C-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alleles
Animals
Argonaute Proteins / metabolism*
Cell Line, Tumor
Cell Membrane / metabolism
Cellular Senescence
Disease Progression
ErbB Receptors / metabolism
Female
Gene Expression Regulation, Neoplastic
Genotype
Humans
Male
Mice
Mice, Transgenic
Neoplasm Transplantation
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology
Phosphorylation
Protein Binding
Proto-Oncogene Proteins p21(ras) / metabolism*
Signal Transduction
Tumor Suppressor Protein p53 / metabolism

Substances

AGO2 protein, human
Ago2 protein, mouse
Argonaute Proteins
KRAS protein, human
TP53 protein, human
Tumor Suppressor Protein p53
EGFR protein, human
EGFR protein, mouse
ErbB Receptors
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding