Endo180 and basement membrane stiffness induce OXPHOS and neoplasia in aging prostate epithelia

During prostate aging collagen-IV is modified by advanced glycation end-products (AGEs), inducing crosslinking of the basement membrane that surround glandular acini. AGEs-rich (stiff) basement membrane is sensed by the Endo180 receptor that triggers epithelial-to-mesenchymal transition, limiting survival in prostate cancer patients. Our finding that basement membrane stiffness and Endo180 cooperate to rewire epithelia for mitochondrial oxidative phosphorylation and gene signatures involved in sustaining evasion of growth suppressors, promotion of cell proliferation, resisting cell death, inflammation, invasion and metastasis -without affecting genome instability- pinpoints this biomechanical event in age-related neoplasia. Endo180 was found to couple to oxidative phosphorylation in Gleason 6, and uncouple in Gleason ≥7 tumors, revealing a switch that predicts transition from indolent to aggressive prostate cancer. This identifies Endo180 as a specific biomarker for the early stage of this age-related cancer that could help phase out unnecessary treatment and improve the quality of life and survival of patients.