An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 04, 2020
- Source ID
- 10.1038/s41467-020-16309-2
Entities
People
- Alice Xu
- Andrew Goodrum
- Chandan Kumar-sinha
- Howard C. Crawford
- Ingrid J. Apel
- Jean Ching-yi Tien
- Jessica Waninger
- Jiaqi Shi
- John J. Tesmer
- Malay Mody
- Pankaj Vats
- Rahul Mannan
- Ronald F Siebenaler
- Sanjana Eyunni
- Seema Chugh
- Sethuramasundaram Pitchiaya
- Stephanie J. Ellison
- Sunita Shankar
- Sylvia Zelenka-wang
- Vijaya L. Dommeti
- Xiao-Ming Wang
- Xuhong Cao
- Yuping Zhang
Organizations
- National Institutes of Health
- United States Department of Defense