Abstract
Fibroblasts are a major component of the microenvironment of most solid tumours. Recent research elucidated a large heterogeneity and plasticity of activated fibroblasts, indicating that their role in cancer initiation, growth and metastasis is complex and context-dependent. Here, we performed genome-wide expression analysis comparing fibroblasts in normal, inflammatory and tumour- associated skin. Cancer-associated fibroblasts (CAFs) exhibit a fibrotic gene signature in wound- induced tumours, demonstrating persistent extracellular matrix (ECM) remodelling within these tumours. A top upregulated gene in CAFs encodes for PRSS35, a protease capable of collagen remodelling. Ablation of PRSS35 in mouse models of wound- or chemically-induced tumorigenesis resulted in aberrant collagen composition in the ECM and increased tumour incidence, indicating that fibrotic enzymes can protect skin from tumour formation. Finally, we show that in human squamous cell carcinomas, PRSS35 is uniquely expressed in stroma of high-grade tumours. Our results indicate that fibrotic enzymes expressed by CAFs can regulate squamous tumour initiation by remodelling the ECM.
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