title: The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma.
abstract: Melanoma, an aggressive skin malignancy with increasing lifetime risk, originates from melanocytes (MCs) that are in close contact with surrounding epidermal keratinocytes (KCs). How the epidermal microenvironment controls melanomagenesis remains poorly understood. In this study, we identify an unexpected non-cell autonomous role of epidermal polarity proteins, molecular determinants of cytoarchitecture, in malignant melanoma. Epidermal Par3 inactivation in mice promotes MC dedifferentiation, motility, and hyperplasia and, in an autochthonous melanoma model, results in increased tumor formation and lung metastasis. KC-specific Par3 loss up-regulates surface P-cadherin that is essential to promote MC proliferation and phenotypic switch toward dedifferentiation. In agreement, low epidermal PAR3 and high P-cadherin expression correlate with human melanoma progression, whereas elevated P-cadherin levels are associated with reduced survival of melanoma patients, implying that this mechanism also drives human disease. Collectively, our data show that reduced KC Par3 function fosters a permissive P-cadherin-dependent niche for MC transformation, invasion, and metastasis. This reveals a previously unrecognized extrinsic tumor-suppressive mechanism, whereby epithelial polarity proteins dictate the cytoarchitecture and fate of other tissue-resident cells to suppress their malignant outgrowth.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany.|Center for Molecular Medicine Cologne, University of Cologne, 50923 Köln, Germany.
authors.forename: Melina
authors.identifier: 0000-0001-5005-4232
authors.initials: M
authors.lastname: Mescher
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany.|Center for Molecular Medicine Cologne, University of Cologne, 50923 Köln, Germany.
authors.forename: Peter
authors.identifier: 0000-0002-7089-8448
authors.initials: P
authors.lastname: Jeong
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany.|Center for Molecular Medicine Cologne, University of Cologne, 50923 Köln, Germany.
authors.forename: Sina K
authors.initials: SK
authors.lastname: Knapp
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany.|Department of Dermatology, University of Cologne, 50923 Köln, Germany.
authors.forename: Matthias
authors.identifier: 0000-0002-0012-2601
authors.initials: M
authors.lastname: Rübsam
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Saynisch
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany.|Center for Molecular Medicine Cologne, University of Cologne, 50923 Köln, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Kranen
authors.affiliation: Laboratory of Immunodermatology, Department of Dermatology, Venereology, and Allergology, University Hospital Essen, and German Cancer Consortium, Partner Site Essen/Düsseldorf, West German Cancer Center, University of Duisburg-Essen, 45122 Essen, Germany.|Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Jennifer
authors.identifier: 0000-0003-2362-5831
authors.initials: J
authors.lastname: Landsberg
authors.affiliation: Department of Dermatology, University of Cologne, 50923 Köln, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Schlaak
authors.affiliation: Department of Dermatology, University of Cologne, 50923 Köln, Germany.
authors.forename: Cornelia
authors.identifier: 0000-0002-3989-0536
authors.initials: C
authors.lastname: Mauch
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.|Department of Dermatology, University Hospital Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Thomas
authors.identifier: 0000-0001-7146-0934
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany.|Department of Dermatology, University of Cologne, 50923 Köln, Germany.|Center for Molecular Medicine Cologne, University of Cologne, 50923 Köln, Germany.
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923 Köln, Germany sandra.iden@uk-koeln.de.|Center for Molecular Medicine Cologne, University of Cologne, 50923 Köln, Germany.
authors.forename: Sandra
authors.identifier: 0000-0003-2333-9827
authors.initials: S
authors.lastname: Iden
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015820:Cadherins / Q000032:analysis; D002450:Cell Communication; D018797:Cell Cycle Proteins / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D004817:Epidermis / Q000737:chemistry*; D006801:Humans; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; D025521:Tumor Suppressor Proteins