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An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development.
Shankar, Sunita; Tien, Jean Ching-Yi; Siebenaler, Ronald F; Chugh, Seema; Dommeti, Vijaya L; Zelenka-Wang, Sylvia; Wang, Xiao-Ming; Apel, Ingrid J; Waninger, Jessica; Eyunni, Sanjana; Xu, Alice; Mody, Malay; Goodrum, Andrew; Zhang, Yuping; Tesmer, John J; Mannan, Rahul; Cao, Xuhong; Vats, Pankaj; Pitchiaya, Sethuramasundaram; Ellison, Stephanie J; Shi, Jiaqi; Kumar-Sinha, Chandan; Crawford, Howard C; Chinnaiyan, Arul M.
Affiliation
  • Shankar S; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Tien JC; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Siebenaler RF; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Chugh S; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Dommeti VL; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Zelenka-Wang S; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Wang XM; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Apel IJ; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Waninger J; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Eyunni S; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Xu A; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Mody M; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Goodrum A; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Zhang Y; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Tesmer JJ; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Mannan R; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Cao X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Vats P; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Pitchiaya S; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Ellison SJ; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Shi J; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Kumar-Sinha C; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Crawford HC; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Chinnaiyan AM; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
Nat Commun ; 11(1): 2817, 2020 06 04.
Article in En | MEDLINE | ID: mdl-32499547
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Proto-Oncogene Proteins p21(ras) / Argonaute Proteins Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Nat Commun Year: 2020 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Proto-Oncogene Proteins p21(ras) / Argonaute Proteins Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Nat Commun Year: 2020 Document type: Article