PREreview of Transcription Factor EB regulates phosphatidylinositol-3-phosphate levels on endomembranes and alters lysosome positioning in the bladder cancer model

This research article gives a new perspective on lysosomal metabolism and positioning in the context of tumorigenesis.

The key findings of the paper include the differential distribution of lysosomes in cancer cell types compared to normal urothelium cells, they show the lysosomal compartment to be more peripherally localized in cancer cell types. The authors have used different bladder cancer cell lines varying from low to high grade cancer cells. The use of multiple cell lines suggests conserved mechanism of action and not just a random event. They also found this phenotype to me more prominent in higher grade cancer cells. The paper talks about the mechanism of the same, where a set of immunohistochemistry studies show that the mTORC1 which resides on these cellular compartment cross talks with its downstream effector TFEB and ultimately regulates its positioning. This transcription factor then regulates proteins like protrudin via interacting with PI3P. Any form of interaction studies would been helpful to determine the mode of action and regulation between these proteins to govern lysosomal positioning. I also felt that checking the status of microtubular proteins which are the prime players of organelle positioning would have been helpful.

Overall this paper adds new information on lysosomes which are important for sensing of nutrients and metabolism, to the cancer biology field where both the phenomenon is required for malignant growth.

Since this paper exclusively talks about PI3P, and studies have shown other phosphoinositides species in regulating lysosomal positioning, it would have been interesting if some experiments also included the possibility of changing pi45p2 levels and its downstream effects. The reason for emphasising pi45p2 is the inverse relationship between the mucolipin channels and pi45p2 levels.