Metabolic readouts of tumor instructed normal tissues (TINT) identify aggressive prostate cancer subgroups for tailored therapy

Background Prostate cancer (PC) diagnosis relies on histopathological examination of prostate biopsies, which is restricted by insufficient sampling of all tumors present. Including samples from non-PC but tumor instructed normal tissues (TINT) may increase the diagnostic power by exploring the adaptive responses in benign tissues near tumors. Methods Here, we applied high-resolution magic angle spinning nuclear magnetic resonance (HR MAS NMR) to identify metabolomic biomarkers with high diagnostic value in benign prostate tissues near low/high-grade tumors. Results Benign samples near high-grade tumors (B ISUP 3+4) exhibit altered metabolic profiles compared to those close to low-grade tumors (B ISUP 1+2). The levels of six metabolites were significantly different between the two groups; myo-inositol, lysine, serine and combined signal of lysine/leucine/arginine were increased in benign samples near high-grade tumors (B ISUP 3+4) compared to near low-grade tumors (B ISUP 1+2), while levels of ethanolamine and lactate decreased. Additionally, we revealed metabolic differences in non-cancer tissues as a function of their distance to the nearest tumor. Eight metabolites (glutathione, glutamate, combined signal of glutamate/glutamine - glx, glycerol, inosine, ethanolamine, serine and arginine) significantly differentiated between benign tissue located close to the tumor (d ≤ 5 mm) compared to those far away (d ≥ 1 cm). Conclusions Our HR MAS NMR-based approach identified metabolic signatures in prostate biopsies that reflect the response of benign tissues to the presence of nearby located tumors in the same prostate and confirmed the power of the TINT concept for improved PC diagnostics and understanding of tumor-tissue interactions. ### Competing Interest Statement The authors have declared no competing interest. * CPMG : Carr-Purcell-Meiboom-Gill DRE : digital rectal exam Glx : glutamate/glutamine HR MAS NMR : High Resolution Magic Angle Spinning Nuclear Magnetic Resonance IP6 : inositol hexaphosphate ISUP : International Society of Urological Pathology LOX : lysyl oxidase MSMB : microseminoprotein-beta PC : Prostate cancer PCA : Principal Component Analysis PSA : Prostate-Specific Antigen TINT : tumor instructed normal tissues