VIB Center for Inflammation Research, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
EMBO Rep. 2021 May 5;22(5):e51573. doi: 10.15252/embr.202051573. Epub 2021 Mar 29.
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.
成纤维细胞是大多数实体瘤微环境的主要组成部分。最近的研究阐明了激活的成纤维细胞具有很大的异质性和可塑性，表明它们在癌症的发生、生长和转移中的作用是复杂的且依赖于背景。在这里，我们进行了全基因组表达分析，比较了正常、炎症和肿瘤相关皮肤中的成纤维细胞。癌相关成纤维细胞（CAF）在诱导性肿瘤中表现出纤维化基因特征，表明这些肿瘤内持续存在细胞外基质（ECM）重塑。在小鼠 CAF 中上调幅度最高的基因编码 PRSS35，这是一种能够进行胶原重塑的蛋白酶。在人类皮肤中，我们观察到 PRSS35 仅在高级别鳞状细胞癌的基质中表达。在创伤或化学诱导肿瘤发生的小鼠模型中敲除 PRSS35 会导致 ECM 中胶原组成异常和肿瘤发生率增加。我们的结果表明，CAF 表达的纤维化酶可以通过重塑 ECM 来调节鳞状肿瘤的起始。
