Universität zu Köln

Mescher, Melina, Jeong, Peter, Knapp, Sina K., Ruebsam, Matthias, Saynisch, Michael, Kranen, Marina, Landsberg, Jennifer ORCID: 0000-0001-8029-3883, Schlaak, Max, Mauch, Cornelia, Tueting, Thomas, Niessen, Carien M. and Iden, Sandra ORCID: 0000-0003-2333-9827 (2017). The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma. J. Exp. Med., 214 (2). S. 339 - 359. NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-9538

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mescher, Melina UNSPECIFIED UNSPECIFIED UNSPECIFIED Jeong, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Knapp, Sina K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruebsam, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Saynisch, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Kranen, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Landsberg, Jennifer UNSPECIFIED orcid.org/0000-0001-8029-3883 UNSPECIFIED Schlaak, Max UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Tueting, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Niessen, Carien M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Iden, Sandra UNSPECIFIED orcid.org/0000-0003-2333-9827 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-240967
DOI:	10.1084/jem.20160596
Journal or Publication Title:	J. Exp. Med.
Volume:	214
Number:	2
Page Range:	S. 339 - 359
Date:	2017
Publisher:	ROCKEFELLER UNIV PRESS
Place of Publication:	NEW YORK
ISSN:	1540-9538
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language JUVENILE MACULAR DYSTROPHY; P-CADHERIN EXPRESSION; MURINE HAIR FOLLICLE; P120 CATENIN; INVASIVE MELANOMA; ADHESION MOLECULE; CANCER GENOMICS; STEM-CELLS; MICE; MOUSE Multiple languages Immunology; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24096