{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T05:12:01Z","timestamp":1778303521599,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100025520","name":"Medical Research Future Fund","doi-asserted-by":"crossref","award":["90256045"],"award-info":[{"award-number":["90256045"]}],"id":[{"id":"10.13039\/501100025520","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009321","name":"iCare Focus","doi-asserted-by":"publisher","award":["53808543"],"award-info":[{"award-number":["53808543"]}],"id":[{"id":"10.13039\/501100009321","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DW Henderson AOM Bequest"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Pleural mesothelioma (PM) is characterised by often rapid therapeutic failure and chemotherapy resistance. While terminal resistance is well studied, the initial transition into a drug-tolerant phenotype remains poorly understood. Methods: We established patient-derived organoids (PDOs) from malignant pleural effusions to model this transition. Cisplatin-tolerant lines were generated via repeated incremental exposure to cisplatin and compared to time-matched treatment-naive controls using RNA sequencing and Seahorse XFe96 metabolic flux analysis. Results: Integrated profiling suggested that the route to tolerance may be influenced by the underlying mutational profile. In this cohort, all BAP1-retained models (including those with KRAS mutations or MTAP loss) adopted an elevated basal metabolic hybrid phenotype, significantly upregulating baseline oxidative phosphorylation and glycolysis to fuel survival mechanisms. Conversely, BAP1-deficient models entered a hypometabolic state of dormancy, characterised by baseline bioenergetic suppression and reduced Ki-67 proliferation. Transcriptomic analysis identified a vesicular transport signature (SYNGR3, VPS52, PROM2) in plastic models, suggesting altered membrane trafficking as a potential survival strategy. Conclusions: Our findings demonstrate that mesothelioma therapeutic escape is not a uniform process. Identifying these patient-specific metabolic and transcriptomic trajectories via 3D PDOs provides a hypothesis-generating framework to explore potential avenues for future personalised therapy.<\/jats:p>","DOI":"10.3390\/cancers18101500","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:39:47Z","timestamp":1778150387000},"page":"1500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A High-Fidelity Patient-Derived Organoid Platform Recapitulates the Dynamic Metabolic Landscape of Cisplatin Tolerance in Mesothelioma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4566-5036","authenticated-orcid":false,"given":"Zivile","family":"Useckaite","sequence":"first","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashleigh J.","family":"Hocking","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren A.","family":"Mortimer","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1880-474X","authenticated-orcid":false,"given":"John","family":"Salamon","sequence":"additional","affiliation":[{"name":"South Australian Genomics Centre, SAHMRI (South Australian Health and Medical Research Institute), North Terrace, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Lee","sequence":"additional","affiliation":[{"name":"South Australian Genomics Centre, SAHMRI (South Australian Health and Medical Research Institute), North Terrace, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2861-5774","authenticated-orcid":false,"given":"Yazad","family":"Irani","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5318-8374","authenticated-orcid":false,"given":"Lucy","family":"Franzon","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arya L.","family":"Arul","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3252-2519","authenticated-orcid":false,"given":"Sarita","family":"Prabhakaran","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8976-4714","authenticated-orcid":false,"given":"Sonja","family":"Klebe","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia"},{"name":"Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide, SA 5042, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1200\/JCO-24-02425","article-title":"Treatment of Pleural Mesothelioma: ASCO Guideline Update","volume":"43","author":"Kindler","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1158\/1078-0432.CCR-20-4037","article-title":"Alterations in BAP1 Are Associated with Cisplatin Resistance through Inhibition of Apoptosis in Malignant Pleural Mesothelioma","volume":"27","author":"Oehl","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1016\/j.jtho.2021.07.017","article-title":"Mechanism of Drug Tolerant Persister Cancer Cells: The Landscape and Clinical Implication for Therapy","volume":"16","author":"Mikubo","year":"2021","journal-title":"Thorac. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"L756","DOI":"10.1152\/ajplung.00078.2025","article-title":"Use of patient-derived organoids for pleural mesothelioma 3-D modeling","volume":"329","author":"Volpini","year":"2025","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1002\/biot.200700228","article-title":"Recent advances in three-dimensional multicellular spheroid culture for biomedical research","volume":"3","author":"Lin","year":"2008","journal-title":"Biotechnol. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.cell.2020.10.027","article-title":"Persistent Cancer Cells: The Deadly Survivors","volume":"183","author":"Shen","year":"2020","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cell.2010.02.027","article-title":"A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations","volume":"141","author":"Sharma","year":"2010","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/s41568-020-00302-4","article-title":"Non-genetic mechanisms of therapeutic resistance in cancer","volume":"20","author":"Marine","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10690","DOI":"10.1038\/ncomms10690","article-title":"Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells","volume":"7","author":"Ramirez","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nm.4040","article-title":"Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition","volume":"22","author":"Hata","year":"2016","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1038\/s44320-025-00150-0","article-title":"Transition between cell states of sensitivity reveals molecular vulnerability of drug-tolerant cells","volume":"21","author":"Peyre","year":"2025","journal-title":"Mol. Syst. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1126\/science.aao2774","article-title":"Patient-derived organoids model treatment response of metastatic gastrointestinal cancers","volume":"359","author":"Vlachogiannis","year":"2018","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sharick, J.T., Walsh, C.M., Sprackling, C.M., Pasch, C.A., Pham, D.L., Esbona, K., Choudhary, A., Garcia-Valera, R., Burkard, M.E., and McGregor, S.M. (2020). Metabolic Heterogeneity in Patient Tumor-Derived Organoids by Primary Site and Drug Treatment. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00553"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3909","DOI":"10.1073\/pnas.1816391116","article-title":"Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways","volume":"116","author":"Jia","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/s41587-021-00837-3","article-title":"Variability within rare cell states enables multiple paths toward drug resistance","volume":"39","author":"Emert","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/nature13611","article-title":"Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function","volume":"514","author":"Viale","year":"2014","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cedres, S., Valdivia, A., Priano, I., Rocha, P., Iranzo, P., Pardo, N., Martinez-Marti, A., and Felip, E. (2025). BAP1 Mutations and Pleural Mesothelioma: Genetic Insights, Clinical Implications, and Therapeutic Perspectives. Cancers, 17.","DOI":"10.3390\/cancers17091581"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.5858\/arpa.2023-0304-RA","article-title":"Guidelines for Pathologic Diagnosis of Mesothelioma: 2023 Update of the Consensus Statement From the International Mesothelioma Interest Group","volume":"148","author":"Husain","year":"2024","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107542","DOI":"10.1016\/j.lungcan.2024.107542","article-title":"Establishing mesothelioma patient-derived organoid models from malignant pleural effusions","volume":"191","author":"Hocking","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1007\/s10120-021-01206-4","article-title":"Establishment of oxaliplatin-resistant gastric cancer organoids: Importance of myoferlin in the acquisition of oxaliplatin resistance","volume":"24","author":"Harada","year":"2021","journal-title":"Gastric Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41587-020-0439-x","article-title":"The nf-core framework for community-curated bioinformatics pipelines","volume":"38","author":"Ewels","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/s41592-018-0046-7","article-title":"Bioconda: Sustainable and comprehensive software distribution for the life sciences","volume":"15","author":"Dale","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1093\/bioinformatics\/btx192","article-title":"BioContainers: An open-source and community-driven framework for software standardization","volume":"33","author":"Uszkoreit","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nbt.3820","article-title":"Nextflow enables reproducible computational workflows","volume":"35","author":"Chatzou","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.jtho.2022.04.008","article-title":"BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study","volume":"17","author":"Louw","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1310478","DOI":"10.1155\/2017\/1310478","article-title":"Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis?","volume":"2017","author":"Pulford","year":"2017","journal-title":"Dis. Markers"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Trassl, L., and Stathopoulos, G.T. (2022). KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player. Cancers, 14.","DOI":"10.3390\/cancers14174303"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/s41431-023-01448-z","article-title":"Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome","volume":"31","author":"Lalloo","year":"2023","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Brown, C.W., Amante, J.J., Chhoy, P., Elaimy, A.L., Liu, H., Zhu, L.J., Baer, C.E., Dixon, S.J., and Mercurio, A.M. (2019). Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export. Dev. Cell, 51.","DOI":"10.1016\/j.devcel.2019.10.007"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/ncb3129","article-title":"EARP is a multisubunit tethering complex involved in endocytic recycling","volume":"17","author":"Schindler","year":"2015","journal-title":"Nat. Cell. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1158\/2767-9764.CRC-21-0135","article-title":"Tumor Cell Extrinsic Synaptogyrin 3 Expression as a Diagnostic and Prognostic Biomarker in Head and Neck Cancer","volume":"2","author":"Murphy","year":"2022","journal-title":"Cancer Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature24297","article-title":"Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition","volume":"551","author":"Hangauer","year":"2017","journal-title":"Nature"},{"key":"ref_34","first-page":"1","article-title":"Metabolic adaptations in cancer progression","volume":"106","author":"Fendt","year":"2026","journal-title":"Physiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1097\/PAI.0000000000001206","article-title":"Different Frequency and Clinical Role for MTAP Loss in Pleural and Peritoneal Mesothelioma","volume":"32","author":"Davidson","year":"2024","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e185149","DOI":"10.1172\/JCI185149","article-title":"KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer","volume":"135","author":"Yu","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1091\/mbc.11.1.305","article-title":"Vps52p, Vps53p, and Vps54p form a novel multisubunit complex required for protein sorting at the yeast late Golgi","volume":"11","author":"Conibear","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Li, L., Ho, P.W.-L., Liu, H., Pang, S.Y.-Y., Chang, E.E.-S., Choi, Z.Y.-K., Malki, Y., Kung, M.H.-W., Ramsden, D.B., and Ho, S.-L. (2022). Transcriptional Regulation of the Synaptic Vesicle Protein Synaptogyrin-3 (SYNGR3) Gene: The Effects of NURR1 on Its Expression. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073646"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Rehman, S.K., Haynes, J., Collignon, E., Brown, K.R., Wang, Y., Nixon, A.M., Bruce, J.P., Wintersinger, J.A., Mer, A.S., and Lo, E.B. (2021). Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy. Cell, 184.","DOI":"10.1016\/j.cell.2020.11.018"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13073-019-0620-3","article-title":"BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma","volume":"11","author":"Shrestha","year":"2019","journal-title":"Genome Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41698-021-00168-1","article-title":"Patient-derived organoids as a predictive biomarker for treatment response in cancer patients","volume":"5","author":"Wensink","year":"2021","journal-title":"npj Precis. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Tocci, S., and Tsai, J.W. (2025). Protocol for Seahorse 3D Mito Stress assay in patient-derived pediatric brain tumor single neurospheres. bioRxiv.","DOI":"10.64898\/2025.12.03.691986"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1080\/17410541.2025.2581557","article-title":"Patient-Derived Tumour Organoids (PDOs) may help oncologists in clinical practice","volume":"22","author":"Brandi","year":"2025","journal-title":"Pers. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8396","DOI":"10.1038\/s41598-026-38692-4","article-title":"Validation of chemoresistance phenotypes in pleural mesothelioma across 2D, 3D, and in vivo models","volume":"16","author":"Shi","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gao, Y., Julio, M.K.-D., Peng, R.-W., and Dorn, P. (2022). Organoids as a Model for Precision Medicine in Malignant Pleural Mesothelioma: Where Are We Today?. Cancers, 14.","DOI":"10.3390\/cancers14153758"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/10\/1500\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T04:34:02Z","timestamp":1778301242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/10\/1500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cancers18101500"],"URL":"https:\/\/doi.org\/10.3390\/cancers18101500","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]}}}