A High-Fidelity Patient-Derived Organoid Platform Recapitulates the Dynamic Metabolic Landscape of Cisplatin Tolerance in Mesothelioma

Our plain-English summary of A High-Fidelity Patient-Derived Organoid Platform Recapitulates the Dynamic Metabolic Landscape of Cisplatin Tolerance in Mesothelioma, by Z. Useckaite, A.J. Hocking, L.A. Mortimer, et al (Cancers, 2026).

The study

• Authors: Z. Useckaite, A.J. Hocking, L.A. Mortimer, J. Salamon, S. Lee, Y. Irani, L. Franzon, A.L. Arul, S. Prabhakaran, S. Klebe
• Journal: Cancers
• Published: 2026;18(10)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study grew three-dimensional tumour models called organoids from the pleural fluid of four people with pleural mesothelioma. The fluid was collected at Flinders Medical Centre, Adelaide, between May 2021 and July 2024. The study did not examine asbestos exposure. Each organoid line was exposed to slowly rising doses of the chemotherapy drug cisplatin and compared with an untreated line grown alongside it, using gene-activity sequencing and energy-use measurements. BAP1 and MTAP marker status did not change as lines became tolerant. In all four tolerant lines a gene called SYNGR3 was more active (p less than 0.001). The two lines with retained BAP1 raised their basal energy use: one reached 280% of the oxygen use of its untreated pair. The two BAP1-deficient lines lowered oxygen use, by 12% and 31%. Lower Ki-67 growth staining in tolerant lines was not statistically significant (p = 0.065), and the averages the article prints appear to point the other way. The authors concluded that the route to tolerance is not uniform. They stressed that, with four models, the findings are preliminary.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (ex vivo) proof-of-concept study using patient-derived organoids. Cisplatin-tolerant lines were compared with time-matched untreated lines by RNA sequencing and metabolic flux analysis.
• Who was studied: Organoids grown from malignant pleural effusions of 4 people with pleural mesothelioma, collected at Flinders Medical Centre, Adelaide, Australia, May 2021 to July 2024. Table 1 lists 3 males and 1 female, aged 47, 77, 74 and 80 at diagnosis, with survival of 1, 1, 20 and 5 months.
• Exposure: Repeated, increasing concentrations of the chemotherapy drug cisplatin applied to the organoids in the laboratory. Asbestos exposure was not studied.
• Main results:
  • BAP1 and MTAP staining in the organoids matched the patients' diagnostic samples and stayed the same in the cisplatin-tolerant lines. PDO1 retained both markers, PDO2 had MTAP loss, and PDO3 and PDO4 had BAP1 loss with MTAP retained.
  • The text describes lower Ki-67 proliferation in cisplatin-tolerant organoids than in treatment-naive ones, not statistically significant (p = 0.065). However, the printed means are 92.25 (SD 3.86) for tolerant and 76.00 (SD 11.11) for treatment-naive organoids.
  • The two BAP1-deficient lines, PDO3 and PDO4, showed the highest resistance indices (fold-change in IC50). The values themselves are in a supplementary table not included in the text.
  • RNA sequencing found 241 genes differentially expressed between tolerant and untreated organoids.
  • SYNGR3 was upregulated in all four cisplatin-tolerant organoid lines.
  • VPS52 and PROM2 changes differed between lines. PDO4 showed no significant change in either gene.
  • In PDO1 (BAP1 and MTAP retained), the tolerant line's basal oxygen consumption rate reached 280% and its extracellular acidification rate 310% of the treatment-naive pair. No statistical test is reported for these metabolic measurements.
  • In PDO2 (BAP1 retained, MTAP loss), the tolerant line showed increases of 52% and 34% compared with controls. The sentence is garbled; it appears to refer to basal mitochondrial respiration and basal acidification rate respectively.
  • In the BAP1-deficient lines, basal oxygen consumption fell by 12% in PDO3 and by 31% in PDO4 compared with treatment-naive pairs. Acidification rate fell by 12% and 14% respectively.
  • In gene-expression pattern analysis, tolerant and untreated lines clustered closely for PDO2, PDO3 and PDO4. PDO1 showed greater separation between its tolerant and untreated lines.
• The authors' conclusion: The authors concluded that the route to cisplatin tolerance is not uniform and is influenced by the tumour's underlying mutational profile. They presented the organoid platform as hypothesis-generating.
• Limitations the authors state:
  • The main limitation is the small number of organoid models (four).
  • The findings, including the link between BAP1 status and metabolic pattern, are preliminary and not general rules.
  • With four samples, the assumptions of the statistical tests could not be confirmed, so the comparisons are exploratory.
  • Only baseline metabolism could be measured, because the gel the organoids grow in slowed the test chemicals. Maximal respiration was not measured.
  • The gene findings are correlative and need functional testing, for example by gene knockdown.
  • There was no organoid with retained BAP1 and MTAP and normal (wildtype) KRAS.
  • The authors did not test whether tolerance reversed after cisplatin was removed.
  • Germline (inherited) BAP1 status was not determined.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Mesothelioma, Pleural Mesothelioma, Chemotherapy, Pleural Effusion, BAP1, MTAP, Ki-67.

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• Patient-Derived Organoid Models and Precision HIPEC in Diffuse Malignant Peritoneal Mesothelioma: Modeling Heterogeneity to Address Recurrence — E.A. Makris, J.K. Ives, et al. (2026)
• Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1 — F. Ito, K. Kato, et al. (2023)
• Metabolomics of a cell line-derived xenograft model reveals circulating metabolic signatures for malignant mesothelioma — Y. Gao, Z. Dai, et al. (2022)

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