Cancer-associated fibroblasts: activin A adds another string to their bow

Non-melanoma skin cancer (NMSC) is characterized by a strong desmoplastic reaction, largely responsible for cancer aggressiveness. Within the tumour microenvironment, cancer-associated fibroblasts (CAFs) play a key role in tumour progression, secretion of extracellular matrix proteins and recruitment of immunosuppressive cells. However, pathways involved in acquisition of CAF phenotype remain unclear. In this issue of EMBO Molecular Medicine, Cangkrama et al describe a new mechanism of fibroblast activation in squamous cell carcinoma. Cancer cell-secreted activin A induces a tumour-promoting phenotype in the fibroblast compartment, with distinct properties compared to TGF-β-activated fibroblasts. Activin A reprograms fibroblasts through transcriptional regulation of mDia2 and reduction of nuclear p53, which favours CAF marker expression, and increases tumour growth and migration. Inhibition of this pathway shows promising results in different models and could offer a new therapeutic strategy in NMSC.