Distinct contributions of EMT states to colorectal cancer ferroptosis

To investigate how tumor heterogeneity involved in ferroptosis mediated by the physical microenvironment is a breakthrough in solving the therapeutic resistance of colorectal cancer (CRC). Based on the three-dimensional (3D) fibrin gel model, we identified four stages of epithelial-mesenchymal transition (EMT) in vitro that are synergistically regulated by mechanical cues and E-cadherin (ECAD) expression with varying degrees of resistance to ferroptosis. Mechanistically, we elucidated that 3D cells undergoing hybrid EMT fought ferroptosis via WNT/β-catenin-GPXs/ferritin signaling axis, while cells of a late-hybrid EMT state relied on adhesion tension forced mitohormesis to reach super defense against ferroptosis. This work deconstructed the distinct contributions of tumor heterogeneity to ferroptosis from an EMT perspective and uncovered the biomechanical weakness of therapeutic resistance. These findings, in conjunction with tumoroids, were expected to serve for future ferroptosis-based personalized diagnosis and treatment of CRC.