title: Tyrosine 23 phosphorylation-dependent cell-surface localization of annexin A2 is required for invasion and metastases of pancreatic cancer.
abstract: The aggressiveness of pancreatic ductal adenocarcinoma (PDA) is characterized by its high metastatic potential and lack of effective therapies, which is the result of a lack of understanding of the mechanisms involved in promoting PDA metastases. We identified Annexin A2 (ANXA2), a member of the Annexin family of calcium-dependent phospholipid binding proteins, as a new molecule that promotes PDA invasion and metastases. We found ANXA2 to be a PDA-associated antigen recognized by post-treatment sera of patients who demonstrated prolonged survival following treatment with a PDA-specific vaccine. Cell surface ANXA2 increases with PDA development and progression. Knockdown of ANXA2 expression by RNA interference or blocking with anti-ANXA2 antibodies inhibits in vitro invasion of PDA cells. In addition, post-vaccination patient sera inhibits in vitro invasion of PDA cells, suggesting that therapeutic anti-ANXA2 antibodies are induced by the vaccine. Furthermore, cell-surface localization of ANXA2 is tyrosine 23 phosphorylation-dependent; and tyrosine 23 phosphorylation is required for PDA invasion. We demonstrated that tyrosine 23 phosphorylation resulting in surface expression of ANXA2 is required for TGFβ-induced, Rho-mediated epithelial-mesenchymal transition (EMT), linking the cellular function of ANXA2 which was previously shown to be associated with small GTPase-regulated cytoskeletal rearrangements, to the EMT process in PDA. Finally, using mouse PDA models, we showed that shRNA knock-down of ANXA2, a mutation at tyrosine 23, or anti-ANXA2 antibodies, inhibit PDA metastases and prolong mouse survival. Thus, ANXA2 is part of a novel molecular pathway underlying PDA metastases and a new target for development of PDA therapeutics.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. lzheng6@jhmi.edu
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Kelly
authors.initials: K
authors.lastname: Foley
authors.forename: Lanqing
authors.initials: L
authors.lastname: Huang
authors.forename: Ashley
authors.initials: A
authors.lastname: Leubner
authors.forename: Guanglan
authors.initials: G
authors.lastname: Mo
authors.forename: Kelly
authors.initials: K
authors.lastname: Olino
authors.forename: Barish H
authors.initials: BH
authors.lastname: Edil
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mizuma
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.forename: Dung T
authors.initials: DT
authors.lastname: Le
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.forename: Peter B
authors.initials: PB
authors.lastname: Illei
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation; D034622:RNA Interference; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: D017306:Annexin A2; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D014443:Tyrosine