Polarity proteins in melanocyte homeostasis and melanoma

Coworkers: Sina Knapp, Sebastian Holdermann, Annika Graband, Peter Jeong

We recently demonstrated a context-dependent dual role of the ubiquitously expressed polarity protein Par3 in non-melanoma skin tumorigenesis, with both pro-oncogenic and tumor-suppressive function depending on the tumor type (see Iden et al., Cancer Cell 2012; Mescher & Iden, 2015). In this project, we investigated molecular mechanisms underlying the control of tissue architecture and malignant disease. 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. We here identified 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 revealed 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 (see Mescher, Jeong et al., JEM 2017).