Polarity signalling in epithelial cancers

Profound alterations in adhesion and cell polarity are hallmarks of cancer and implicated in tumor growth, invasion and metastasis (Mescher & Iden, 2015). Functional evidence for a role of polarity proteins in cancer, however, is still sparse and largely limited to cultured cells and invertebrate studies.

Non-melanoma skin cancer is among the most common cancers worldwide with a still increasing incidence due to longer life expectancy and sun exposure. Interestingly, the tumor environment plays a decisive role in skin cancer progression. We here asked whether polarity protein dysfunction in mammals affects processes underlying tumorigenesis and metastasis. Our work demonstrated a causal link between mammalian polarity protein dysfunction and the formation and progression of cancer. Loss of epidermal Par3 in a Ras-driven in vivo tumor model resulted in impaired papilloma formation, with increased apoptosis and reduced proliferation, indicating that Par3 mediates its tumor-promoting activity through regulation of growth and survival. Strikingly, however, Par3 mutant mice also displayed predisposition to keratoacanthoma and increased invasiveness. These findings highlighted a context-dependent role of Par3 in epidermal tumors, and strongly challenged the view of cell polarity as a tumor-suppressive entity (Iden et al., 2012). Our follow-up work further identified genetic interactions between Par3 and the Ser/Thr kinase aPKC in these Ras-driven tumors but also independent functions of either protein in distinct stages during tumorigenesis (Vorhagen, Kleefisch et al., 2017).