title: AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D.
abstract: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers largely due to disseminated disease at the time of presentation. Here, we investigated the role and mechanism of action of the metastasis-associated protein anterior gradient 2 (AGR2) in the pathogenesis of pancreatic cancer. AGR2 was induced in all sporadic and familial pancreatic intraepithelial precursor lesions (PanIN), PDACs, circulating tumor cells, and metastases studied. Confocal microscopy and flow cytometric analyses indicated that AGR2 localized to the endoplasmic reticulum (ER) and the external surface of tumor cells. Furthermore, induction of AGR2 in tumor cells regulated the expression of several ER chaperones (PDI, CALU, RCN1), proteins of the ubiquitin-proteasome degradation pathway (HIP2, PSMB2, PSMA3, PSMC3, and PSMB4), and lysosomal proteases [cathepsin B (CTSB) and cathepsin D (CTSD)], in addition to promoting the secretion of the precursor form pro-CTSD. Importantly, the invasiveness of pancreatic cancer cells was proportional to the level of AGR2 expression. Functional downstream targets of the proinvasive activity of AGR2 included CTSB and CTSD in vitro, and AGR2, CTSB, and CTSD were essential for the dissemination of pancreatic cancer cells in vivo. Taken together, the results suggest that AGR2 promotes dissemination of pancreatic cancer and that its cell surface targeting may permit new strategies for early detection as well as therapeutic management.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Laurent
authors.initials: L
authors.lastname: Dumartin
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Whiteman
authors.forename: Mark E
authors.initials: ME
authors.lastname: Weeks
authors.forename: Deepak
authors.initials: D
authors.lastname: Hariharan
authors.forename: Branko
authors.initials: B
authors.lastname: Dmitrovic
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Brentnall
authors.forename: Mary P
authors.initials: MP
authors.lastname: Bronner
authors.forename: Roger M
authors.initials: RM
authors.lastname: Feakins
authors.forename: John F
authors.initials: JF
authors.lastname: Timms
authors.forename: Caroline
authors.initials: C
authors.lastname: Brennan
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Tatjana
authors.initials: T
authors.lastname: Crnogorac-Jurcevic
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002401:Cathepsin B / Q000235:genetics / Q000502:physiology*; D002402:Cathepsin D / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D009088:Mucoproteins; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011506:Proteins / Q000502:physiology*; D020543:Proteome; D015027:Zebrafish
chemical_list: C502296:AGR2 protein, human; D000954:Antigens, Surface; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D020543:Proteome; D002401:Cathepsin B; D002402:Cathepsin D