Synergistic mechanotransduction via the ΔP–EPPK1/DDR2– PI3K/AKT axis drives cell invasion and migration

The mechanical forces within solid tumors, including solid stress and intracellular pressure, are known to contribute to the tumor microenvironment, yet how cancer cells integrate these combined cues to promote invasion is poorly understood. Here, we develop a composite in vitro model coupling cell crowding with osmotic modulation to mimic the transmembrane pressure differential (ΔP) of the tumor microenvironment. We demonstrate that crowding synergizes with hypotonic stress to elevate ΔP, which robustly enhances invasive migration. Mechanistically, ΔP activates a novel signaling axis centered on the coordinated upregulation of the cytoskeletal linker EPPK1 and the collagen receptor DDR2. This EPPK1/DDR2 hub converges on PI3K/AKT pathway activation, which in turn drives a dual pro-invasive program: upregulation of Vimentin to induce an epithelial-mesenchymal transition state and enhanced expression of MMP24 to facilitate extracellular matrix degradation. Pharmacological inhibition of either EPPK1 or DDR2 blocks ΔP-driven invasion, confirming their essential role. Our work delineates a complete mechanotransduction pathway—the ΔP-EPPK1/DDR2-PI3K/AKT-Vimentin/MMP24 axis—that translates integrated mechanical stress into invasive behavior, providing a mechanistic framework for therapeutic strategies targeting the mechanical niche of solid tumors.