title: Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides.
abstract: Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane which can be provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. HDs have been explored in normal and cancer pancreatic cells, and patient samples. Unique cancer cell models where HD assembly can be pharmacologically manipulated by somatostatin/sst2 signaling have been then used to investigate the role and molecular mechanisms of dynamic HD during pancreatic carcinogenesis. We surprisingly report the presence of mature type-1 HDs comprising the integrin α6β4 and bullous pemphigoid antigen BP180 in the human pancreatic ductal epithelium. Importantly, HDs are shown to disassemble during pancreatic carcinogenesis. HD breakdown requires phosphoinositide 3-kinase (PI3K)-dependent induction of the matrix-metalloprotease MMP-9, which cleaves BP180. Consequently, integrin α6β4 delocalizes to the cell-leading edges where it paradoxically promotes cell migration and invasion through S100A4 activation. As S100A4 in turn stimulates MMP-9 expression, a vicious cycle maintains BP180 cleavage. Inactivation of this PI3K-MMP-9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion. We conclude that mature type-1 HDs are critical anchoring structures for the pancreatic ductal epithelium whose disruption, upon PI3K activation during carcinogenesis, provokes pancreatic cancer cell migration and invasion.
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Laval
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: H
authors.initials: H
authors.lastname: Laklai
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Fanjul
authors.affiliation: INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Pucelle
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: H
authors.initials: H
authors.lastname: Laurell
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Billon-Galés
authors.affiliation: Services d'Anatomie et Cytologie Pathologique of Hôpital Rangueil, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Le Guellec
authors.affiliation: Services d'Anatomie et Cytologie Pathologique of Hôpital Rangueil, Toulouse, France.
authors.forename: M-B
authors.initials: MB
authors.lastname: Delisle
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Sonnenberg
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Susini
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Pyronnet
authors.affiliation: 1] INSERM UMR 1037, Laboratoire d'excellence Toulouse Cancer (labex TOUCAN), Equipe labellisée Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France [2] Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Bousquet
mesh_terms: D001324:Autoantigens / Q000378:metabolism; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D022002:Hemidesmosomes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000473:pathology*; D024041:Non-Fibrillar Collagens / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034622:RNA Interference; D017481:Receptors, Somatostatin / Q000378:metabolism; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D024041:Non-Fibrillar Collagens; D019869:Phosphatidylinositol 3-Kinases; D017481:Receptors, Somatostatin; D000097805:Collagen Type XVII; C093733:somatostatin receptor 2