title: Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties.
abstract: The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.
authors.affiliation: Oncogenesis, Stress and Signaling Laboratory, ERL440 Inserm, Université de Rennes 1, Rennes, France.|Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.|INSERM U1218, Actions for onCogenesis understanding and Target Identification in ONcology (ACTION), Bordeaux, France.|Bergonié Cancer Institute, Bordeaux, France.
authors.forename: Delphine
authors.identifier: 0000-0001-7566-5670
authors.initials: D
authors.lastname: Fessart
authors.affiliation: Université de Bordeaux, Bordeaux, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Domblides
authors.affiliation: Oncogenesis, Stress and Signaling Laboratory, ERL440 Inserm, Université de Rennes 1, Rennes, France.|Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
authors.forename: Tony
authors.initials: T
authors.lastname: Avril
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.affiliation: Hôpital Haut-Lévêque, Bordeaux, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Begueret
authors.affiliation: Animalerie mutualisée, Université de Bordeaux, Bordeaux, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Pineau
authors.affiliation: INSERM U1218, Actions for onCogenesis understanding and Target Identification in ONcology (ACTION), Bordeaux, France.|Bergonié Cancer Institute, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Malrieux
authors.affiliation: Université de Bordeaux, Bordeaux, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dugot-Senant
authors.affiliation: Bergonié Cancer Institute, Bordeaux, France.|Site de Recherche Intégrée sur le Cancer, Bordeaux Recherche Intégrée en Oncologie, Bordeaux, France.
authors.forename: Carlo
authors.initials: C
authors.lastname: Lucchesi
authors.affiliation: Oncogenesis, Stress and Signaling Laboratory, ERL440 Inserm, Université de Rennes 1, Rennes, France.|Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
authors.forename: Eric
authors.identifier: 0000-0001-5855-4522
authors.initials: E
authors.lastname: Chevet
authors.affiliation: INSERM U1218, Actions for onCogenesis understanding and Target Identification in ONcology (ACTION), Bordeaux, France.|Bergonié Cancer Institute, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
authors.forename: Frederic
authors.identifier: 0000-0002-4600-7633
authors.initials: F
authors.lastname: Delom
mesh_terms: D063646:Carcinogenesis; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000201:enzymology / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D009088:Mucoproteins; D009369:Neoplasms / Q000503:physiopathology*; D015513:Oncogene Proteins; D011506:Proteins / Q000378:metabolism*
chemical_list: C502296:AGR2 protein, human; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins
keywords: AGR2; cancer; cancer biology; cell biology; endoplasmic reticulum; human; mouse; organoids; protein disulphide isomerase