Transcription Factor EB regulates phosphatidylinositol-3-phosphate levels on endomembranes and alters lysosome positioning in the bladder cancer model
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Abstract
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.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7031105.
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 …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7031105.
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.
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