Endo180 and basement membrane stiffness induce OXPHOS and neoplastic transformation in aging prostate epithelia.

Abstract

During prostate aging collagen-IV is modified by advanced glycation end-products, inducing crosslinking of the basement membrane surrounding glandular acini. Basement membrane stiffness sensed by Endo180 disrupts its suppressor complex with CD147, triggering epithelial-to-mesenchymal transition and limiting survival in prostate cancer patients. Here we report basement membrane stiffness and Endo180 cooperate in rewiring epithelia for mitochondrial oxidative phosphorylation (OXPHOS) and growth suppressor evasion, cell proliferation promotion, cell death resistance, inflammation, invasion and metastasis without affecting genome instability, highlighting a non-oncogenic biomechanical event in age-related neoplasia. Endo180-CD147 complex coupled to OXPHOS in Gleason 6 and in Gleason ≥7 tumors Endo180 uncoupled from CD147-OXPHOS, identifying a bio-switch for invasive cancer. Endo180 correlated with patient age in normal tissue, Gleason 6 and 7, but not Gleason 8 tumors, suggesting biological age unleashes its suppression of tumorigenesis. Application of Endo180-based diagnostics in age-related glandular cancers could inform treatment decisions, improving quality of life and survival.