{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T19:28:19Z","timestamp":1780774099228,"version":"3.54.1"},"reference-count":67,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells10051188","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T03:08:12Z","timestamp":1620875292000},"page":"1188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Extracellular Acidification Induces Lysosomal Dysregulation"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1492-9473","authenticated-orcid":false,"given":"Bryce","family":"Ordway","sequence":"first","affiliation":[{"name":"Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8888-7747","authenticated-orcid":false,"given":"Robert J.","family":"Gillies","sequence":"additional","affiliation":[{"name":"Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7744-6161","authenticated-orcid":false,"given":"Mehdi","family":"Damaghi","sequence":"additional","affiliation":[{"name":"Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"},{"name":"Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The Metabolism of Tumors in the Body","volume":"8","author":"Warburg","year":"1927","journal-title":"J. Gen. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.molmet.2019.07.006","article-title":"Monocarboxylate transporters in cancer","volume":"33","author":"Payen","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1476-5586(03)80037-4","article-title":"Extracellular Acidification Alters Lysosomal Trafficking in Human Breast Cancer Cells","volume":"5","author":"Glunde","year":"2003","journal-title":"Neoplasia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1083\/jcb.201507112","article-title":"The position of lysosomes within the cell determines their luminal pH","volume":"212","author":"Johnson","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1083\/jcb.108.3.855","article-title":"Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH","volume":"108","author":"Heuser","year":"1989","journal-title":"J. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/nrc1478","article-title":"Why do cancers have high aerobic glycolysis?","volume":"4","author":"Gatenby","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg Effect: How Does it Benefit Cancer Cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1158\/0008-5472.CAN-11-2474","article-title":"Regulation of Monocarboxylate Transporter MCT1 Expression by p53 Mediates Inward and Outward Lactate Fluxes in Tumors","volume":"72","author":"Boidot","year":"2012","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1091\/mbc.E14-04-0868","article-title":"Inactivation of GSK3beta and activation of NF-kappaB pathway via Axl represents an important mediator of tumorigenesis in esophageal squamous cell carcinoma","volume":"26","author":"Paccez","year":"2015","journal-title":"Mol. Biol. Cell."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1158\/1541-7786.MCR-11-0569","article-title":"Hypoxia Stabilizes GAS6\/Axl Signaling in Metastatic Prostate Cancer","volume":"10","author":"Mishra","year":"2012","journal-title":"Mol. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.neo.2018.08.005","article-title":"AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking","volume":"20","author":"Maacha","year":"2018","journal-title":"Neoplasia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/s41416-018-0216-5","article-title":"Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo","volume":"119","author":"Lee","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8752","DOI":"10.1038\/ncomms9752","article-title":"Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane","volume":"6","author":"Damaghi","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/S0006-2952(99)00022-2","article-title":"pH and drug resistance. I. functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines","volume":"57","author":"Raghunand","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1242\/jcs.196287","article-title":"Mechanisms and functions of lysosome positioning","volume":"129","author":"Pu","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/ncb2393","article-title":"Pulling together and pulling apart: Collective cargo movement in eukaryotic cells","volume":"13","author":"Mullins","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1083\/jcb.113.2.261","article-title":"pH-induced microtubule-dependent redistribution of late endosomes in neuronal and epithelial cells","volume":"113","author":"Parton","year":"1991","journal-title":"J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/s41422-018-0080-0","article-title":"STAT3 associates with vacuolar H+-ATPase and regulates cytosolic and lysosomal pH","volume":"28","author":"Liu","year":"2018","journal-title":"Cell Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-05261-x","article-title":"Systems analysis of intracellular pH vulnerabilities for cancer therapy","volume":"9","author":"Persi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/jcb.240350103","article-title":"Estrogen-induced lysosomal proteases secreted by breast cancer cells: A role in carcinogenesis?","volume":"35","author":"Rochefort","year":"1987","journal-title":"J. Cell. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1101\/gad.1407406","article-title":"Distinct roles for cysteine cathepsin genes in multistage tumorigenesis","volume":"20","author":"Gocheva","year":"2006","journal-title":"Genes Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1083\/jcb.85.3.839","article-title":"Chloroquine inhibits lysosomal enzyme pinocytosis and enhances lysosomal enzyme secretion by impairing receptor recycling","volume":"85","author":"Grubb","year":"1980","journal-title":"J. Cell Biol."},{"key":"ref_23","first-page":"6517","article-title":"Pericellular pH affects distribution and secretion of cathepsin B in malignant cells","volume":"54","author":"Rozhin","year":"1994","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1126\/science.1207056","article-title":"mTORC1 Senses Lysosomal Amino Acids Through an Inside-Out Mechanism That Requires the Vacuolar H+-ATPase","volume":"334","author":"Zoncu","year":"2011","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.cell.2018.05.009","article-title":"Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR","volume":"174","author":"Walton","year":"2018","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.trecan.2019.07.002","article-title":"Interplay between Circadian Clock and Cancer: New Frontiers for Cancer Treatment","volume":"5","author":"Sulli","year":"2019","journal-title":"Trends Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.cmet.2015.09.003","article-title":"MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells","volume":"22","author":"Altman","year":"2015","journal-title":"Cell Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.molcel.2019.05.009","article-title":"Lysosome Positioning Influences mTORC2 and AKT Signaling","volume":"75","author":"Jia","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_29","first-page":"905","article-title":"Purification, characterization and molecular cloning of human hepatic lysosomal acid lipase","volume":"219","author":"Ameis","year":"1994","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1093\/oxfordjournals.jbchem.a131034","article-title":"Degradation of Rod Outer Segment Proteins by Cathepsin D","volume":"78","author":"Hayasaka","year":"1975","journal-title":"J. Biochem."},{"key":"ref_31","first-page":"100","article-title":"Exocytosis of active cathepsin B enzyme activity at pH 7.0, inhibition and molecular mass","volume":"264","author":"Linebaugh","year":"1999","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1242\/jcs.115.3.599","article-title":"pH-dependent regulation of lysosomal calcium in macrophages","volume":"115","author":"Christensen","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e15887","DOI":"10.7554\/eLife.15887","article-title":"The endoplasmic reticulum, not the pH gradient, drives calcium refilling of lysosomes","volume":"5","author":"Garrity","year":"2016","journal-title":"eLife"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ceca.2009.12.007","article-title":"Aberrant Ca2+ handling in lysosomal storage disorders","volume":"47","author":"Kiselyov","year":"2010","journal-title":"Cell Calcium"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wu, Y., Huang, P., and Dong, X.-P. (2021). Lysosomal Calcium Channels in Autophagy and Cancer. Cancers, 13.","DOI":"10.3390\/cancers13061299"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1158\/0008-5472.CAN-11-3881","article-title":"Chronic Autophagy Is a Cellular Adaptation to Tumor Acidic pH Microenvironments","volume":"72","author":"Wojtkowiak","year":"2012","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"43654","DOI":"10.18632\/oncotarget.9661","article-title":"Overexpression of transient receptor potential mucolipin-2 ion channels in gliomas: Role in tumor growth and progression","volume":"7","author":"Morelli","year":"2016","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1016\/j.febslet.2009.12.056","article-title":"Mucolipins: Intracellular TRPML1-3 channels","volume":"584","author":"Cheng","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3389\/fcell.2019.00302","article-title":"Endolysosomal Ca(2+) Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis","volume":"7","author":"Alharbi","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0092-8674(01)00421-4","article-title":"Plasma Membrane Repair Is Mediated by Ca2+-Regulated Exocytosis of Lysosomes","volume":"106","author":"Reddy","year":"2001","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1083\/jcb.200708010","article-title":"Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis","volume":"180","author":"Idone","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1083\/jcb.200208154","article-title":"Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells","volume":"159","author":"Jaiswal","year":"2002","journal-title":"J. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Castro-Gomes, T., Corrotte, M., Tam, C., and Andrews, N.W. (2016). Plasma Membrane Repair Is Regulated Extracellularly by Proteases Released from Lysosomes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152583"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1016\/j.jmb.2020.04.003","article-title":"Molecular Links between the Circadian Clock and the Cell Cycle","volume":"432","author":"Farshadi","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41598-017-00393-4","article-title":"Lysosomal activity maintains glycolysis and cyclin E1 expression by mediating Ad4BP\/SF-1 stability for proper steroidogenic cell growth","volume":"7","author":"Syu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_46","first-page":"1","article-title":"Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation","volume":"11","author":"Stahl","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1158\/0008-5472.CAN-16-2693","article-title":"Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA","volume":"77","author":"Jdey","year":"2017","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1080\/15384101.2016.1231287","article-title":"Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA","volume":"15","author":"Lewis","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Ye, C.J., Sharpe, Z., Alemara, S., MacKenzie, S., Liu, G., Abdallah, B., Horne, S., Regan, S., and Heng, H.H. (2019). Micronuclei and Genome Chaos: Changing the System Inheritance. Genes, 10.","DOI":"10.3390\/genes10050366"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e08160","DOI":"10.7554\/eLife.08160","article-title":"The vacuole\/lysosome is required for cell-cycle progression","volume":"4","author":"Jin","year":"2015","journal-title":"eLife"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1086\/669883","article-title":"The aesthetics of laboratory inscription: Claude Bernard\u2019s Cahier Rouge","volume":"104","author":"Sattar","year":"2013","journal-title":"Isis"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fonc.2020.00304","article-title":"Integrative Analysis of Breast Cancer Cells Reveals an Epithelial-Mesenchymal Transition Role in Adaptation to Acidic Microenvironment","volume":"10","author":"Sadeghi","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Cortini, M., Armirotti, A., Columbaro, M., Longo, D., Pompo, G., Cannas, E., Maresca, A., Errani, C., Longhi, A., and Righi, A. (2021). Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target. Cancers, 13.","DOI":"10.3390\/cancers13020311"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-020-01815-4","article-title":"Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo","volume":"40","author":"Rauschner","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1242\/jcs.071233","article-title":"Lipid map of the mammalian cell","volume":"124","author":"Meer","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1007\/s11064-010-0337-6","article-title":"Biological Function of the Cellular Lipid BMP\u2014BMP as a Key Activator for Cholesterol Sorting and Membrane Digestion","volume":"36","author":"Gallala","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_57","first-page":"243","article-title":"Expression and functionality of TRPV1 in breast cancer cells","volume":"8","author":"Weber","year":"2016","journal-title":"Breast Cancer: Targets Ther."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Yang, M.H., Jung, S.H., Sethi, G., and Ahn, K.S. (2019). Pleiotropic Pharmacological Actions of Capsazepine, a Synthetic Analogue of Capsaicin, against Various Cancers and Inflammatory Diseases. Molecules, 24.","DOI":"10.3390\/molecules24050995"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1038\/sj.emboj.7600177","article-title":"A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons","volume":"23","author":"Diochot","year":"2004","journal-title":"EMBO J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e2806","DOI":"10.1038\/cddis.2017.189","article-title":"ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca2+\/RhoA pathway","volume":"8","author":"Zhu","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-13666-9","article-title":"Glioblastoma cancer stem cell lines express functional acid sensing ion channels ASIC1a and ASIC3","volume":"7","author":"Tian","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.peptides.2013.06.003","article-title":"A novel sea anemone peptide that inhibits acid-sensing ion channels","volume":"53","author":"Salceda","year":"2014","journal-title":"Peptides"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Ordway, B., Tomaszewski, M., Byrne, S., Abrahams, D., Swietach, P., Gillies, R.J., and Damaghi, M. (2020). Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities. Cancers, 13.","DOI":"10.3390\/cancers13010064"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"23847","DOI":"10.1074\/jbc.M002758200","article-title":"Structural basis for the insensitivity of a serine enzyme (palmitoyl-protein thioesterase) to phenylmethyl-sulfonyl fluoride","volume":"275","author":"Das","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1158\/2159-8290.CD-17-0741","article-title":"A Unified Approach to Targeting the Lysosome\u2019s Degradative and Growth Signaling Roles","volume":"7","author":"Rebecca","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1158\/2159-8290.CD-18-0706","article-title":"PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer","volume":"9","author":"Rebecca","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Brun, S., Raymond, E., Bassissi, F., Jilkova, Z.M., Mezouar, S., Rachid, M., Novello, M., Tracz, J., Hama\u00ef, A., and Lalmanach, G. (2020). GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions. bioRxiv.","DOI":"10.1101\/2020.09.30.320010"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1188\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:00:01Z","timestamp":1760162401000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,13]]},"references-count":67,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cells10051188"],"URL":"https:\/\/doi.org\/10.3390\/cells10051188","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,13]]}}}