The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma.
J Exp Med
; 214(2): 339-358, 2017 02.
Article
en En
| MEDLINE
| ID: mdl-28096290
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Ciclo Celular
/
Proteínas Supresoras de Tumor
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Epidermis
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Melanoma
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Proteínas de la Membrana
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Exp Med
Año:
2017
Tipo del documento:
Article
País de afiliación:
Alemania