Posted: Thursday, April 13, 2023
Cell lines representing high-grade bladder cancers seem to exhibit scattered, peripheral lysosomal compartment positioning compared with normal urothelial cells. This may be the result of the activation of transcription factor EB (TFEB), which leads to increased phosphatidylinositol-3-phosphate (PtdIns3P) levels and lysosome dispersion, according to research published in Communications Biology. These findings “conceptually clarify the role of TFEB as [a] regulator of endosomal maturation” and thus may be used “as a potential biomarker for bladder cancer,” according to Kristine Schauer, PhD, of the Centre National de la Recherche Scientifique, Paris, and colleagues.
To observe the role of lysosome organization in bladder cancer, the authors used micropatterns to establish normalized cell cultures representing three low-grade bladder cancers, four high-grade bladder cancers, and primary normal human urothelium cells. They also used three-dimensional imaging and mapping to calculate the nearest neighbor distance of lysosomes in the cells. To further investigate the mechanisms and role of TFEB in the regulation of endosomal PtdIns3P levels, cells were transfected with TFEB–enhanced green fluorescent protein and monitored for localization.
Of the three cell lines representing low-grade bladder cancer, two exhibited centralized lysosomes similar to the normal human urothelium cells. The remining cells lines were characterized by scattered, peripheral lysosome compartments. Additionally, the mammalian target of rapamycin complex 1 (mTORC1) substrate p70-S6 kinase 1 showed stronger phosphorylation in low-grade cancer cells, whereas another mTORC1 substrate, eIF4E binding protein, showed stronger phosphorylation in high-grade cells.
Moreover, the research revealed nuclear translocation of and activation of TFEB, an upstream regulator of PtdIns3P production, in aggressive bladder cancer cells with peripheral lysosomes. Conversely, the depletion of TFEB reversed lysosomal dispersion, confirming the role of TFEB hyperactivation in the peripheral positioning of lysosomes, according to the investigators.
Disclosure: The study authors reported no conflicts of interest.