Field cancerization, the existence of multifocal and recurrent tumours that arise after widespread albeit morphologically not always visible changes in the surrounding tissue, is considered a major driver of very common epithelial cancers. Many of these cancers have high tumour recurrence and mortality rates with often no long-term effective  treatment.

Epithelial tissues are able to maintain functionality and structural integrity in the presence of cancer-causing mutations through mechanisms that are poorly understood. Mutations in key oncogenes and tumor suppressors such as p53 are e.g. common in sun-exposed but physiologically healthy skin. Only a small percentage will proceed to benign lesions such as actinic keratosis defined by field cancerization and inflammation that precedes invasive squamous cell carcinoma (SCC). SCC is the second most frequent skin cancer Despite recent developments in systemic oncology therapies, the current therapy for metastatic SCC is still limited and disease relapse frequently occurs.What prevents evolution to field cancerization and subsequent SCC in skin carrying mutations such as p53 is largely unknown. In the current CMMC project we have identified polarity signaling as barrier for p53 mutant cells to progress to field cancerization and to evolve into SCC.

We aim to explore which settings determine whether polarity signalling, an essential determinant of tissue architecture and stem cell fate, serves a tumour promoting or a tumor inhibitory function. We also ask whether the maintenance of cell and tissue architecture serve as barriers to preserve homeostatic tissue function in the presence of tumor-related mutations such as p53, and how we can exploit this knowledge for novel cancer markers and therapeutic options.

The polarity protein atypical protein kinase C (aPKC)λ is overexpressed in many human tumors and its overexpression associates with poor survival. My laboratory has identified aPKCλ as an important regulator of epidermal homeostasis and stem cell fate (Niessen et al., 2013).Loss of aPKCλ resulted in gradual loss of bulge stem cells and increased differentiation, resulting in premature skin aging. Furthermore, in collaboration with Sandra Iden, we showed that aPKC and Par3 cooperate in promoting Ras-driven two-stage non-melanoma skin carcinogenesis (Vorhagen, Kleefisch et al., 2018).

Mechanistically, we found that aPKCl/Par3 complex promote skin papilloma formation and progression through sustaining growth, survival and inflammatory signalling. This work also identified a Par3 independent role for aPKCl in controlling skin immune homeostasis. Screening a large panel of SCC of the skin revealed not only overexpression of aPKC correlates with increased metastatic risk but also reduced aPKC. In agreement, combined loss of aPKCλ strongly enhanced and accelerated p53-mediated skin carcinogenesis. Unlike p53^ep-/- mice, the aPKCl/p53^epiDKO mice displayed features of field cancerization that precedes the development of multiple locally invasive SCCs, a phenotype that resembles human SCC. Our data show that combined loss of aPKC/p53 induces epidermal inflammatory signals that recruit macrophages essential for field cancerization and SCC formation. Thus, aPKC polarity signaling provides a critical boundary to skin field cancerization and SCC formation to guarantee physiological tissue function (Persa et al., submitted). We are now using these mice as a model for field cancerization to repurpose new drugs for SCC.