Iden, Sandra - A 3

Cell polarization is crucial for a variety of processes such as oriented cell division, adhesion or migration. How cyto-architecture is coordinated in the context of tumor formation and progression is an intriguing question in cancer cell biology. This project aims to investigate how conserved polarity regulators control melanoma skin cancer by extrinsic and intrinsic mechanisms. An ultimate goal is to elucidate clinical strategies targeting the polarity machinery for prevention and treatment of skin malignancies.

Melanoma originates from melanocytes that are in close contact with surrounding epidermal keratinocytes. Though keratinocyte-melanocyte cross-talk is essential for skin photoprotection it is unknown whether the epidermal microenvironment directly controls melanomagenesis. In this project we identified an unexpected non-cell autonomous role of epidermal polarity proteins in malignant melanoma. In an autochthonous mouse melanoma model epidermal Par3 inactivation resulted in increased tumor formation and lung metastasis. Keratinocyte-specific Par3 loss disturbs melanocyte-keratinocyte interactions resulting in melanocyte proliferation and phenotypic switch. In agreement, low epidermal PAR3 levels correlate with human melanoma progression, implying that PAR3 dysfunction also drives human disease. Collectively, reduced Par3 function fosters a permissive niche for melanocyte transformation, invasion and metastasis. This reveals a previously unrecognized extrinsic tumor-suppressive mechanism, whereby epithelial polarity proteins dictate the cyto-architecture and fate of other tissue-resident cells to suppress their malignant outgrowth.

Next to extrinsic mechanisms underlying melanoma we also aim to understand how polarity regulators control the intrinsic shape and function of melanocytes and melanoma cells. To investigate in vivo processes that direct melanoma invasion and metastasis, in collaboration with the Department of Ophthalmology we developed a novel syngeneic model for metastatic conjunctival melanoma. Immune-competent C57BL/6 mice show tumor-associated lymphangiogenesis with development of metastatic tumors (Schlereth et al., 2015). This model now offers new possibilities to study the pathobiology of tumor growth, invasion, and mechanisms of metastatic tumor spread, and provides a robust system to explore new immune-based and antilymphangiogenic treatment modalities of this malignancy. Ongoing studies address the role of polarity networks therein.

Next to important roles in tumorigenesis we found that Par3 controls the formation of the inside-out skin permeability barrier, epidermal differentiation, mitotic spindle orientation, and hair follicle stem cell maintenance (Ali et al., 2016), thereby preventing premature skin aging. Interestingly, mice with impaired mTORC2 function exhibit skin barrier defects, with Par3 failing to polarize during early stages of barrier formation (Ding et al., 2016). These findings suggest that mTOR signalling acts upstream of polarity protein-mediated skin barrier formation.

Our work has provided new mechanistic insight into cellular cross-talk in the context of formation and progression of melanoma, an aggressive skin malignancy with increasing lifetime risk. Despite recent progress in immune and targeted therapies, diverse resistance mechanisms pose an unresolved major problem preventing long-term treatment success. Melanoma cells display tremendous plasticity to reversibly switch on developmental and differentiation programs, fuelling disease progression. Therefore, future efforts will focus on understanding key principles underlying melanoma plasticity, which will be fundamental to develop effective clinical strategies.