Fibrotic enzymes modulate wound‐induced skin tumorigenesis

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 mouse CAFs encodes for PRSS35, a protease capable of collagen remodelling. In human skin, we observed PRSS35 expression uniquely in the stroma of high-grade squamous cell carcinomas. Ablation of PRSS35 in mouse models of wound-or chemically-induced tumorigenesis resulted in aberrant collagen composition in the ECM and increased tumour incidence. Our results indicate that fibrotic enzymes expressed by CAFs can regulate squamous tumour initiation by remodelling the ECM.

Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment

“…Fidler and Hart ( Hart and Fidler, 1980 ) showed a century later that melanoma cells spread to lung or ovarian tissue but not to renal tissue independent of the primary tumor site and concluded that tumor growth indeed depends on properties of the tumor cells (seeds) and host (soil). We now understand that tumor cells affect stromal cells and vice versa, and that the crosstalk between different tumor compartments contributes to tumor progression ( Bhowmick et al, 2004a , b ; Kaplan et al, 2005 ; Stuelten et al, 2008 ; Van Hove et al, 2021 ).…”

Molecular profiling of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in cellular and LSL-Kras G12D/+; Trp53 fl/+; Pdx1-Cre (KPC) pancreatic cancer model

“…It belongs to the trypsin class of serine proteases [38]. Though originally identified as a novel mouse ovary-selective gene [38, 39] it is involved in collagen remodeling [40]. PRSS35 ablation in mouse models of chemically induced tumorigenesis demonstrated aberrant collagen composition in the extra cellular matrix (ECM) and increased tumor incidence [40].…”

“…Though originally identified as a novel mouse ovary-selective gene [38, 39] it is involved in collagen remodeling [40]. PRSS35 ablation in mouse models of chemically induced tumorigenesis demonstrated aberrant collagen composition in the extra cellular matrix (ECM) and increased tumor incidence [40]. MicroRNA 1224 and adenosylhomocysteinase pseudogene 5 gene sets are downregulated by Sel only.…”

Activation of Fibroblasts in Skin Cancer

“…Microarray analysis on fibroblasts isolated from dysplastic skin regions in the keratin-14 human papillomavirus 16 (K14-HPV16) mouse model showed that CAFs express a pro-inflammatory gene signature (Erez et al, 2010), while fibroblasts isolated from squamous tumours in a mouse model expressing constitutively active MEK1 (MAP kinase kinase-1) showed a fibrotic signature (Van Hove et al, 2021). Interestingly, the latter study showed that overexpression of inflammatory genes is present in pre-cancerous inflamed skin, while the fibrotic gene signature dominates in CAFs, implicating that the relative contribution of these populations shifts during skin cancer progression.…”

“…MMP-13 is essential for the invasive growth of SCC cells in a murine tumour transplantation model (Vosseler et al 2009). Other ECM remodelling enzymes that can influence skin tumorigenesis are PRSS35 and ADAMTS4 (Van Hove et al 2021;Rao et al 2013).…”