We analyzed clinical associations between serum HE4 levels, tumor stiffness, and stromal fibroblast activation markers; evaluated the direct effects of recombinant HE4 on fibroblast activation and matrix contractility in vitro; explored the regulatory role of tumor cell-derived HE4 on fibroblast activation; and assessed the impact of HE4 suppression on ECM remodeling and tumor growth in subcutaneous xenograft models. This evidence concerns the gene WFDC2 and neoplasm.