The Lysosome in Cancer: From Pathogenesis to Therapy

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Intracellular and Plasma Membranes".

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Editors

Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
Interests: autophagy; lysosomal cathepsins; epigenetics; cancer; cell metabolism; cancer cell dormancy; nanomedicine
Cell Death and Metabolicm Unit, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
Interests: lysosomes; cancer; metabolism; lipids; membranes; signaling; pH regulation; cationic amphiphilic drugs
School of Medicine, Wayne State University, Detroit, MI, USA
Interests: lysosomal cathepsins; imaging; extracellular proteolysis; invasion and metastasis; angiogenesis

Topical Collection Information

Dear Colleagues,

This Topical Collection of Cells collects original research and review articles addressing the role of lysosomes and of lysosomal proteins in the pathogenesis of cancer, and their possible exploitation as therapeutic targets.

The lysosome represents the final station of a network of vesicles that traffic intracellular and extracellular materials through the pathways of autophagy, phagocytosis, and endocytosis. Its subcellular localization dynamically switches from a perinuclear position near the Golgi Complex to a more peripheral position in response to metabolic signals.

Thanks to over sixty acid hydrolytic enzymes, the lysosome can degrade all the biomolecules delivered to it from inside and outside the cell, thus modeling the macromolecular composition of the cell and of the extracellular environment.

The accidental or induced release of lysosomal proteolytic enzymes (cathepsins) within the cytoplasm can trigger cell death, while their exocytosis causes the dissolution of the extracellular matrix.

Given the role in cell survival and cell death, cell homeostasis, and cell-to-cell and cell-to-extracellular environment communications, not surprisingly, lysosome positioning and function are altered in cancer cells. Failure of fusion of lysosomes with autophagosomes compromises the homeostatic and anticancer functions of autophagy. On the other hand, lysosome fusion with the plasmamembrane results in the acidification and remodeling of the extracellular matrix that is instrumental to cancer cell metastatisation.

The evidence indicates that lysosomal malfunctioning is involved in cancer pathogenesis and progression. Accordingly, lysosomal proteins in cancer may serve as diagnostic and prognostic markers, as well as therapeutic targets.

Prof. Dr. Ciro Isidoro
Prof. Dr. Marja Jäättelä
Prof. Dr. Bonnie F. Sloane
Collection Editors

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Keywords

  • lysosomal hydrolases
  • invasion and metastasis
  • cell death
  • prognostic marker
  • therapeutic target
  • chemoresistance
  • lysosome imaging
  • lysosome in nanomedicine
  • epigenetics
  • pH homeostasis
  • metabolic signaling

Published Papers (6 papers)

2022

Jump to: 2021, 2020

21 pages, 3803 KiB  
Article
Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells
by Ditte L. Fogde, Cristina P. R. Xavier, Kristina Balnytė, Lya K. K. Holland, Kamilla Stahl-Meyer, Christoffel Dinant, Elisabeth Corcelle-Termeau, Cristina Pereira-Wilson, Kenji Maeda and Marja Jäättelä
Cells 2022, 11(24), 4079; https://doi.org/10.3390/cells11244079 - 16 Dec 2022
Cited by 4 | Viewed by 1591
Abstract
Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter [...] Read more.
Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely partakes in the mechanism by which ursolic acid kills cancer cells. Furthermore, we find that combining treatment with ursolic acid and cationic amphiphilic drugs can significantly enhance the degree of lysosomal membrane permeabilization and cell death in breast cancer cells. Full article
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20 pages, 2909 KiB  
Article
Lysosomal Changes in Mitosis
by Jonathan Stahl-Meyer, Lya Katrine Kauffeldt Holland, Bin Liu, Kenji Maeda and Marja Jäättelä
Cells 2022, 11(5), 875; https://doi.org/10.3390/cells11050875 - 03 Mar 2022
Cited by 4 | Viewed by 2976
Abstract
The recent discovery demonstrating that the leakage of cathepsin B from mitotic lysosomes assists mitotic chromosome segregation indicates that lysosomal membrane integrity can be spatiotemporally regulated. Unlike many other organelles, structural and functional alterations of lysosomes during mitosis remain, however, largely uncharted. Here, [...] Read more.
The recent discovery demonstrating that the leakage of cathepsin B from mitotic lysosomes assists mitotic chromosome segregation indicates that lysosomal membrane integrity can be spatiotemporally regulated. Unlike many other organelles, structural and functional alterations of lysosomes during mitosis remain, however, largely uncharted. Here, we demonstrate substantial differences in lysosomal proteome, lipidome, size, and pH between lysosomes that were isolated from human U2OS osteosarcoma cells either in mitosis or in interphase. The combination of pharmacological synchronization and mitotic shake-off yielded ~68% of cells in mitosis allowing us to investigate mitosis-specific lysosomal changes by comparing cell populations that were highly enriched in mitotic cells to those mainly in the G1 or G2 phases of the cell cycle. Mitotic cells had significantly reduced levels of lysosomal-associated membrane protein (LAMP) 1 and the active forms of lysosomal cathepsin B protease. Similar trends were observed in levels of acid sphingomyelinase and most other lysosomal proteins that were studied. The altered protein content was accompanied by increases in the size and pH of LAMP2-positive vesicles. Moreover, mass spectrometry-based shotgun lipidomics of purified lysosomes revealed elevated levels of sphingolipids, especially sphingomyelin and hexocylceramide, and lysoglyserophospholipids in mitotic lysosomes. Interestingly, LAMPs and acid sphingomyelinase have been reported to stabilize lysosomal membranes, whereas sphingomyelin and lysoglyserophospholipids have an opposite effect. Thus, the observed lysosomal changes during the cell cycle may partially explain the reduced lysosomal membrane integrity in mitotic cells. Full article
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2021

Jump to: 2022, 2020

10 pages, 1897 KiB  
Brief Report
Extracellular Acidification Induces Lysosomal Dysregulation
by Bryce Ordway, Robert J. Gillies and Mehdi Damaghi
Cells 2021, 10(5), 1188; https://doi.org/10.3390/cells10051188 - 13 May 2021
Cited by 9 | Viewed by 3318
Abstract
Many invasive cancers emerge through a years-long process of somatic evolution, characterized by an accumulation of heritable genetic and epigenetic changes and the emergence of increasingly aggressive clonal populations. In solid tumors, such as breast ductal carcinoma, the extracellular environment for cells within [...] Read more.
Many invasive cancers emerge through a years-long process of somatic evolution, characterized by an accumulation of heritable genetic and epigenetic changes and the emergence of increasingly aggressive clonal populations. In solid tumors, such as breast ductal carcinoma, the extracellular environment for cells within the nascent tumor is harsh and imposes different types of stress on cells, such as hypoxia, nutrient deprivation, and cytokine inflammation. Acidosis is a constant stressor of most cancer cells due to its production through fermentation of glucose to lactic acid in hypoxic or normoxic regions (Warburg effect). Over a short period of time, acid stress can have a profound effect on the function of lysosomes within the cells exposed to this environment, and after long term exposure, lysosomal function of the cancer cells can become completely dysregulated. Whether this dysregulation is due to an epigenetic change or evolutionary selection has yet to be determined, but understanding the mechanisms behind this dysregulation could identify therapeutic opportunities. Full article
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14 pages, 2128 KiB  
Review
The Contribution of Lysosomes to DNA Replication
by Joanna Maria Merchut-Maya and Apolinar Maya-Mendoza
Cells 2021, 10(5), 1068; https://doi.org/10.3390/cells10051068 - 30 Apr 2021
Cited by 5 | Viewed by 3015
Abstract
Lysosomes, acidic, membrane-bound organelles, are not only the core of the cellular recycling machinery, but they also serve as signaling hubs regulating various metabolic pathways. Lysosomes maintain energy homeostasis and provide pivotal substrates for anabolic processes, such as DNA replication. Every time the [...] Read more.
Lysosomes, acidic, membrane-bound organelles, are not only the core of the cellular recycling machinery, but they also serve as signaling hubs regulating various metabolic pathways. Lysosomes maintain energy homeostasis and provide pivotal substrates for anabolic processes, such as DNA replication. Every time the cell divides, its genome needs to be correctly duplicated; therefore, DNA replication requires rigorous regulation. Challenges that negatively affect DNA synthesis, such as nucleotide imbalance, result in replication stress with severe consequences for genome integrity. The lysosomal complex mTORC1 is directly involved in the synthesis of purines and pyrimidines to support DNA replication. Numerous drugs have been shown to target lysosomal function, opening an attractive avenue for new treatment strategies against various pathologies, including cancer. In this review, we focus on the interplay between lysosomal function and DNA replication through nucleic acid degradation and nucleotide biosynthesis and how these could be exploited for therapeutic purposes. Full article
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18 pages, 2944 KiB  
Article
Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma
by Katharina Körholz, Johannes Ridinger, Damir Krunic, Sara Najafi, Xenia F. Gerloff, Karen Frese, Benjamin Meder, Heike Peterziel, Silvia Vega-Rubin-de-Celis, Olaf Witt and Ina Oehme
Cells 2021, 10(5), 1001; https://doi.org/10.3390/cells10051001 - 24 Apr 2021
Cited by 17 | Viewed by 3243
Abstract
Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors [...] Read more.
Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity (Transcription factor EB—TFEB, forkhead boxO—FOXO) and autophagic flux in neuroblastoma cells. In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma. Full article
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2020

Jump to: 2022, 2021

7 pages, 573 KiB  
Brief Report
TRPML1—Emerging Roles in Cancer
by Yiming Yang, Xingjian Zhai and Yassine El Hiani
Cells 2020, 9(12), 2682; https://doi.org/10.3390/cells9122682 - 13 Dec 2020
Cited by 4 | Viewed by 4348
Abstract
The mucolipin-1 (TRPML1) channel maintains lysosomal ionic homeostasis and regulates autophagic flux. Defects of TRPML1 lead to lysosomal storage diseases and neurodegeneration. In this report, we discuss emerging evidence pertaining to differential regulation of TRPML1 signaling pathways in cancer progression with the goal [...] Read more.
The mucolipin-1 (TRPML1) channel maintains lysosomal ionic homeostasis and regulates autophagic flux. Defects of TRPML1 lead to lysosomal storage diseases and neurodegeneration. In this report, we discuss emerging evidence pertaining to differential regulation of TRPML1 signaling pathways in cancer progression with the goal of leveraging the oncogenic potential of TRPML1 to inspire therapeutic interventions. Full article
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