title: AmotL2 disrupts apical-basal cell polarity and promotes tumour invasion.
abstract: The establishment and maintenance of apical-basal cell polarity is essential for the functionality of glandular epithelia. Cell polarity is often lost in advanced tumours correlating with acquisition of invasive and malignant properties. Despite extensive knowledge regarding the formation and maintenance of polarity, the mechanisms that deregulate polarity in metastasizing cells remain to be fully characterized. Here we show that AmotL2 expression correlates with loss of tissue architecture in tumours from human breast and colon cancer patients. We further show that hypoxic stress results in activation of c-Fos-dependent expression of AmotL2 leading to loss of polarity. c-Fos/hypoxia-induced p60 AmotL2 interacts with the Crb3 and Par3 polarity complexes retaining them in large vesicles and preventing them from reaching the apical membrane. The resulting loss of polarity potentiates the response to invasive cues in vitro and in vivo in mice. These data provide a molecular mechanism how hypoxic stress deregulates cell polarity during tumour progression.
authors: 1] Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden [2].
authors: Mahdi
authors: M
authors: Mojallal
authors: 1] Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden [2].
authors: Yujuan
authors: Y
authors: Zheng
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Sara
authors: S
authors: Hultin
authors: 1] Inserm U1068, CRCM, 13009 Marseille, France [2] CNRS UMR7258, CRCM, 13009 Marseille, France [3] Institut Paoli-Calmettes, 13009 Marseille, France [4] Aix-Marseille Université, 13009 Marseille, France.
authors: Stéphane
authors: S
authors: Audebert
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Tanja
authors: T
authors: van Harn
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Per
authors: P
authors: Johnsson
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Claes
authors: C
authors: Lenander
authors: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors: Nicolas
authors: N
authors: Fritz
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors: Christin
authors: C
authors: Mieth
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Martin
authors: M
authors: Corcoran
authors: 1] Inserm U1068, CRCM, 13009 Marseille, France [2] CNRS UMR7258, CRCM, 13009 Marseille, France [3] Institut Paoli-Calmettes, 13009 Marseille, France [4] Aix-Marseille Université, 13009 Marseille, France.
authors: Frédérique
authors: F
authors: Lembo
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Marja
authors: M
authors: Hallström
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Johan
authors: J
authors: Hartman
authors: Institute for Research on Cancer and Ageing of Nice (IRCAN), UMR CNRS 7284-INSERM U1081-UNS, Université de Nice-Sophia-Antipolis, 33 avenue Valombrose, 06189 Nice cedex 2, France.
authors: Nathalie M
authors: NM
authors: Mazure
authors: Department of Internal Medicine D, Division of Molecular Nephrology, University Hospital Muenster, Albert-Schweitzer-Campus 1, A14 D-48149 Muenster, Germany.
authors: Thomas
authors: T
authors: Weide
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Dan
authors: D
authors: Grandér
authors: 1] Inserm U1068, CRCM, 13009 Marseille, France [2] CNRS UMR7258, CRCM, 13009 Marseille, France [3] Institut Paoli-Calmettes, 13009 Marseille, France [4] Aix-Marseille Université, 13009 Marseille, France.
authors: Jean-Paul
authors: JP
authors: Borg
authors: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors: Per
authors: P
authors: Uhlén
authors: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Lars
authors: L
authors: Holmgren
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: C508566:AMOTL2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; C472002:CRB3 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; D016760:Proto-Oncogene Proteins c-fos