A wide variety of tumours are associated with wounding. However, the molecular mechanisms that tip the balance between regeneration and tumour initiation are largely unknown. A crucial component of the skin wound and tumour microenvironment is the fibroblast, a cell-type that has the potential to suppress epithelial growth and cancer. However, following injury or in various tumour types, fibroblasts are activated to stimulate epithelial proliferation. In order to identify tumour-specific ECM remodelling activities in the skin, we previously performed a genome-wide expression study in which we compared the expression profiles of ‘normal’, ‘inflammatory’ and ‘cancer-associated’ fibroblasts isolated from mouse skin. Here, we aim to study two proteases that are highly upregulated by tumour-associated fibroblasts, namely PRSS35 (protease serine 35) and ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin-like motif type 4) and investigate their role in cutaneous regenerative and cancer-initiating responses. By combining flow cytometry, imaging, proteomics approaches and mouse transgenesis, the proposed research is at the cutting edge of gaining new insights into the molecular crosstalk between the skin epithelium, fibroblasts and cells of the immune system during wound healing and neoplastic events. Our findings will contribute to the search for unique candidates for therapeutic targeting of CAFs and the identification of novel biomarkers in cancer.