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Lysosomes orchestrate degradation and recycling of exogenous and endogenous material, thus controlling cellular homeostasis. Little is known how this organelle changes during malignant transformation. We investigate the intracellular landscape of lysosomes in a cellular model of bladder cancer. Employing standardized cell culture on micropatterns we identify a phenotype of peripheral lysosome positioning prevailing in bladder cancer but not normal urothelium. We show that lysosome positioning is controlled by transcription factor EB (TFEB) and that lysosomal dispersion results from TFEB activation downstream of lysosomal Ca ²⁺ release. Remarkably, we find that TFEB regulates phosphatidylinositol-3-phosphate (PtdIns3P) levels on endomembranes which recruit FYVE-domain containing proteins, such as the motor adaptor protrudin, for anterograde movement of lysosomes. Altogether, we uncover lysosome positioning as result of PtdIns3P activation downstream of TFEB as a potential biomarker for bladder cancer. Moreover, we reveal a novel role of TFEB in regulating cellular PtdIns levels, conceptually clarifying the dual role of TFEB as regulator of endosomal maturation and autophagy, two distinct processes controlled by PtdIns3P.

Statement of significance

Here we provide the first atlas for the landscape of the lysosomal compartment in bladder cancer and reveal the mechanistic role of TFEB in regulating endosomal PtdIns3P levels and subsequent lysosomal dispersion. We unveiled lysosomal positioning as a potential biomarker for malignant bladder cancer which might arise as an actionable target for cancer therapy.