The Rab25-ADAMTS5 axis as a previously undescribed mechanism for sensing tumor microenvironment complexity.

The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a critical role in cancer progression. Focusing on ovarian cancer, Yuan et al. reveal an ECM-dependent signaling axis where cancer-associated fibroblasts (CAFs) enhance the invasiveness of cancer cells via Rab25-driven upregulation of the protease ADAMTS5. This process is only triggered in the presence of native ECM. In turn, stimulated cancer cells favor CAF invasiveness through a mechanism that remains to be identified. These findings uncover a bidirectional crosstalk between cancer cells and CAFs and highlight the importance of context-specific in vitro models to decipher ECM-mediated tumor dynamics.