bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2022–11–20
eight papers selected by
Harilaos Filippakis, University of New England
  1. The lysosomal degraders.
  2. MCOLN3/TRPML3 bridges the regulation of autophagosome biogenesis by PtdIns3P and the calcium channel.
  3. Loss of transcription factor TFEB dysregulates the G1/S transition and DNA replication in mammary epithelial cells.
  4. Organelle homeostasis: from cellular mechanisms to disease.
  5. Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning.
  6. Extracellular vesicles as source for the identification of minimally invasive molecular signatures in glioblastoma.
  7. TRPC3 governs the spatiotemporal organization of cellular Ca2+ signatures by functional coupling to IP3 receptors.
  8. Bacterial extracellular vesicle applications in cancer immunotherapy.
  1. Nat Biotechnol. 2022 Nov 17.
    The lysosomal degraders.
    Ken Garber.
      
    DOI:  https://doi.org/10.1038/s41587-022-01594-7
  2. Autophagy. 2022 Nov 16.
    MCOLN3/TRPML3 bridges the regulation of autophagosome biogenesis by PtdIns3P and the calcium channel.
    Yuchen Lei, Daniel J Klionsky.
      In recent years, an increasing number of studies have started to investigate the roles of ions and ion channels in macroautophagy/autophagy. One finding is that calcium regulates multiple stages of autophagy with lysosomal calcium release being important for autophagosome and lysosome fusion. MCOLN3/TRPML3, as a calcium-permeable channel that is located on both lysosomes and autophagosomes, has been suggested as an autophagy regulator and a candidate to provide the calcium for autophagic fusion, but how this channel is activated remains unclear. In a recent article, Kim et al. demonstrate that MCOLN3 is a PtdIns3P downstream effector, and the activation of its channel function is critical for autophagosome biogenesis.
    Keywords:  Autophagosome; MCOLN3/TRPML3; PtdIns3P; calcium; fusion
    DOI:  https://doi.org/10.1080/15548627.2022.2148808
  3. J Biol Chem. 2022 Nov 10. pii: S0021-9258(22)01135-8. [Epub ahead of print] 102692
    Loss of transcription factor TFEB dysregulates the G1/S transition and DNA replication in mammary epithelial cells.
    Logan Slade, Dipsikha Biswas, Petra C Kienesberger, Thomas Pulinilkunnil.
      Triple negative breast cancer (TNBC) poses significant challenges for treatment given the lack of targeted therapies and increased probability of relapse. It is pertinent to identify vulnerabilities in TNBC and develop newer treatments. Our prior research demonstrated that Transcription Factor EB (TFEB) is necessary for TNBC survival by regulating DNA repair, apoptosis signaling, and the cell cycle. However, specific mechanisms by which TFEB targets DNA repair and cell cycle pathways are unclear, and whether these effects dictate TNBC survival is yet to be determined. Here, we find that TFEB knockdown decreased the expression of genes and proteins involved in DNA replication and cell cycle progression in MDA-MB-231 TNBC cells. DNA replication was decreased in cells lacking TFEB, as measured by EdU incorporation. TFEB silencing in non-cancerous MCF10A and MDA-MB-231 cells impaired progression through the S-phase following G1/S synchronization; however, this proliferation defect could not be rescued by co-knockdown of suppressor RB1. Instead, TFEB knockdown reduced origin licensing in G1 and early S-phase MDA-MB-231 cells. TFEB silencing was associated with replication stress in MCF10A but not in TNBC cells. Lastly, we identified that TFEB knockdown renders TNBC cells more sensitive to inhibitors of Aurora Kinase A, a protein facilitating mitosis. Thus, inhibition of TFEB impairs cell cycle progress by decreasing origin licensing, leading to delayed entry into the S-phase, while rendering cells sensitive to Aurora kinase A inhibitors and decreasing TNBC cell viability. In contrast, TFEB silencing in non-cancerous cells is associated with replication stress and leads to G1/S arrest.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102692
  4. FEBS J. 2022 Nov;289(22): 6822-6831
    Organelle homeostasis: from cellular mechanisms to disease.
    Emma Burbridge, Colin Adrain.
      The major criterion that distinguishes eukaryotes from prokaryotes is the presence of organelles in the former. Organelles provide a compartment in which biochemical processes are corralled within bespoke biophysical conditions and act as storage depots, powerhouses, waste storage/recycling units and innate immune signalling hubs. A key challenge faced by organelles is to define, and then retain, their identity; this is mediated by complex proteostasis mechanisms including the import of an organelle-specific proteome, the exclusion of non-organellar proteins and the removal of misfolded proteins via dedicated quality control mechanisms. This Special Issue on Organelle Homeostasis provides an engaging, eclectic, yet integrative, perspective on organelle homeostasis in a range of organelles including those from the secretory and endocytic pathways, mitochondria, the autophagy-lysosomal pathway and the nucleus and its sub-compartments. Some lesser-known organelles including migrasomes (organelles that are released by migrating cells) and GOMED (a Golgi-specific form of autophagy) are also introduced. In the spirit of the principles of organelle biology, we hope you find the reviews in this Issue both encapsulating and captivating, and we thank the authors for their excellent contributions.
    Keywords:  endoplasmic reticulum; mitochondria; nucleus; organelle homeostasis; quality control
    DOI:  https://doi.org/10.1111/febs.16667
  5. Traffic. 2022 Nov 18.
    Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning.
    Mai Ly Tran, Johanna Tüshaus, Yeongho Kim, Bulat R Ramazanov, Swathi Devireddy, Stefan F Lichtenthaler, Shawn M Ferguson, Julia von Blume.
      The trans-Golgi Network (TGN) sorts molecular "addresses" and sends newly synthesized proteins to their destination via vesicular transport carriers. Despite the functional significance of packaging processes at the TGN, the sorting of soluble proteins remains poorly understood. Recent research has shown that the Golgi resident protein Cab45 is a significant regulator of secretory cargo sorting at the TGN. Cab45 oligomerizes upon transient Ca2+ influx, recruits soluble cargo molecules (clients), and packs them in sphingomyelin-rich transport carriers. However, the identity of client molecules packed into Cab45 vesicles is scarce. Therefore, we used a precise and highly efficient secretome analysis technology called hiSPECs. Intriguingly, we observed that Cab45 deficient cells manifest hypersecretion of lysosomal hydrolases. Specifically, Cab45 deficient cells secrete the unprocessed precursors of prosaposin (PSAP) and progranulin (PGRN). In addition, lysosomes in these cells show an aberrant perinuclear accumulation suggesting a new role of Cab45 in lysosomal positioning. This work uncovers a yet unknown function of Cab45 in regulating lysosomal function.
    Keywords:  Cab45; TGN export; lysosomal hydrolases; progranulin; prosaposin
    DOI:  https://doi.org/10.1111/tra.12873
  6. Semin Cancer Biol. 2022 Nov 11. pii: S1044-579X(22)00218-8. [Epub ahead of print]
    Extracellular vesicles as source for the identification of minimally invasive molecular signatures in glioblastoma.
    Elisabeth Rackles, Patricia Hernández Lopez, Juan M Falcon-Perez.
      The analysis of extracellular vesicles (EVs) as a source of cancer biomarkers is an emerging field since low-invasive biomarkers are highly demanded. EVs constitute a heterogeneous population of small membrane-contained vesicles that are present in most of body fluids. They are released by all cell types, including cancer cells and their cargo consists of nucleic acids, proteins and metabolites and varies depending on the biological-pathological state of the secretory cell. Therefore, EVs are considered as a potential source of reliable biomarkers for cancer. EV biomarkers in liquid biopsy can be a valuable tool to complement current medical technologies for cancer diagnosis, as their sampling is minimally invasive and can be repeated over time to monitor disease progression. In this review, we highlight the advances in EV biomarker research for cancer diagnosis, prognosis, and therapy monitoring. We especially focus on EV derived biomarkers for glioblastoma. The diagnosis and monitoring of glioblastoma still relies on imaging techniques, which are not sufficient to reflect the highly heterogenous and invasive nature of glioblastoma. Therefore, we discuss how the use of EV biomarkers could overcome the challenges faced in diagnosis and monitoring of glioblastoma.
    Keywords:  biomarker; exosome; extracellular vesicle; glioblastoma; liquid biopsy
    DOI:  https://doi.org/10.1016/j.semcancer.2022.11.004
  7. Cell Calcium. 2022 Nov 02. pii: S0143-4160(22)00143-9. [Epub ahead of print]108 102670
    TRPC3 governs the spatiotemporal organization of cellular Ca2+ signatures by functional coupling to IP3 receptors.
    Sanja Curcic, Hazel Erkan-Candag, Johannes Pilic, Roland Malli, Patrick Wiedner, Oleksandra Tiapko, Klaus Groschner.
      Communication between TRPC channels and IP3 receptors (IP3R) is considered pivotal in the generation of spatiotemporal Ca2+signaling patterns. Here we revisited the role of TRPC3-IP3R coupling for local Ca2+ signaling within TRPC3-harbouring micro/nanodomains using R-GECO as a reporter, fused to the channel´s C-terminus. Cytoplasmic Ca2+ changes at TRPC3 originated from both the entry of Ca2+ through the TRPC channel and Ca2+ mobilization via IP3R. Local Ca2+ changes at TRPC3 channels expressed in HEK293 cells were predominantly biphasic with IP3R-dependent initial Ca2+ transients, while exclusively monophasic signals were recorded when all three IP3R isoforms were lacking. Abrogation of Ca2+ entry through TRPC3 by point mutations, which impair Ca2+ permeability (E630Q), cation permeation (E630K), or DAG sensitivity (G652A), promoted microdomain Ca2+ oscillations. Ca2+ signals at E630Q, E630K, and G652A channels featured initial Ca2+ transients along with oscillatory activity. Similarly, when extracellular Ca2+ was omitted, IP3R-mediated Ca2+ transients and Ca2+ oscillations were promoted at the cytoplasmic face of wild-type TRPC3 channels. By contrast, oscillations, as well as initial Ca2+ transients, were virtually lacking, when the TRPC3 channels were sensitized by preexposure to low-level PLC activity. TIRF imaging provided evidence for dynamic colocalization of TRPC3 and IP3R. We suggest that TRPC3-mediated Ca2+ entry controls IP3R activity at ER-PM junctions to determine Ca2+ signaling signatures and enable specificity of downstream signaling.
    Keywords:  ER-PM nanojunction; IP3R; Phospholipase C signaling; TRPC3
    DOI:  https://doi.org/10.1016/j.ceca.2022.102670
  8. Bioact Mater. 2023 Apr;22 551-566
    Bacterial extracellular vesicle applications in cancer immunotherapy.
    Kanika Suri, Anisha D'Souza, Di Huang, Aashray Bhavsar, Mansoor Amiji.
      Cancer therapy is undergoing a paradigm shift toward immunotherapy focusing on various approaches to activate the host immune system. As research to identify appropriate immune cells and activate anti-tumor immunity continues to expand, scientists are looking at microbial sources given their inherent ability to elicit an immune response. Bacterial extracellular vesicles (BEVs) are actively studied to control systemic humoral and cellular immune responses instead of using whole microorganisms or other types of extracellular vesicles (EVs). BEVs also provide the opportunity as versatile drug delivery carriers. Unlike mammalian EVs, BEVs have already made it to the clinic with the meningococcal vaccine (Bexsero®). However, there are still many unanswered questions in the use of BEVs, especially for chronic systemically administered immunotherapies. In this review, we address the opportunities and challenges in the use of BEVs for cancer immunotherapy and provide an outlook towards development of BEV products that can ultimately translate to the clinic.
    Keywords:  Bacterial extracellular vesicles; Cancer immunotherapy; Mammalian extracellular vesicles; Membrane vesicles; Outer membrane vesicles
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.10.024
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