A novel PDX modeling strategy and its application in metabolomics study for malignant pleural mesothelioma

Our plain-English summary of A novel PDX modeling strategy and its application in metabolomics study for malignant pleural mesothelioma, by Z. Chen, C. Yang, Z. Guo, et al (BMC Cancer, 2021).

The study

• Authors: Z. Chen, C. Yang, Z. Guo, S. Song, Y. Gao, D. Wang, W. Mao, J. Liu
• Journal: BMC Cancer
• Published: 2021;21(1):1235
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive carcinoma located in pleural cavity. Due to lack of effective diagnostic biomarkers and therapeutic targets in MPM, the prognosis is extremely poor. Because of difficulties in sample extraction, and the high rate of misdiagnosis, MPM is rarely studied. Therefore, novel modeling methodology is crucially needed to facilitate MPM research.

Methods: A novel patient-derived xenograft (PDX) modeling strategy was designed, which included preliminary screening of patients with pleural thickening using computerized tomography (CT) scan, further reviewing history of disease and imaging by a senior sonographer as well as histopathological analysis by a senior pathologist, and PDX model construction using ultrasound-guided pleural biopsy from MPM patients. Gas chromatography-mass spectrometry-based metabolomics was further utilized for investigating circulating metabolic features of the PDX models. Univariate and multivariate analysis, and pathway analysis were performed to explore the differential metabolites, enriched metabolism pathways and potential metabolic targets.

Results: After screening using our strategy, 5 out of 116 patients were confirmed to be MPM, and their specimens were used for modeling. Two PDX models were established successfully. Metabolomics analysis revealed significant metabolic shifts in PDX models, such as dysregulations in amino acid metabolism, TCA cycle and glycolysis, and nucleotide metabolism.

Conclusions: To sum up, we suggested a novel modeling strategy that may facilitate specimen availability for MM research, and by applying metabolomics in this model, several metabolic features were identified, whereas future studies with large sample size are needed.

© 2021. The Author(s).

In plain English

This laboratory study at Zhejiang Cancer Hospital, China, tested a way to grow human malignant pleural mesothelioma in mice (patient-derived xenograft, or PDX, models). It used ultrasound-guided needle biopsies instead of surgical samples. Of 158 patients with pleural thickening on CT scans reviewed between March 2018 and December 2019, 116 had biopsies. Ten biopsies from suspected mesothelioma were implanted in mice, and 5 were confirmed as mesothelioma. Two grew into working models: an epithelioid tumor from a 55-year-old man and a sarcomatoid tumor from an 85-year-old woman. Both donors were recorded as having no asbestos exposure. The authors then identified 209 substances in the blood serum of tumor-bearing mice and untreated control mice. Compared with controls, 81 substances differed in the first model and 24 in the second. Kynurenine, succinic acid, pyruvic acid, uric acid, uridine and inosine were raised in both. The authors concluded the method could make mesothelioma samples easier to obtain, and said larger studies are needed. They noted that genetic mutation information was available for only one patient.

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 and animal study: developing patient-derived xenograft (PDX) mouse models from ultrasound-guided pleural biopsies, followed by GC-MS-based serum metabolomics in the mice
• Who was studied: 158 patients with pleural thickening reviewed at Zhejiang Cancer Hospital, China, from March 1, 2018 to December 30, 2019. 42 were excluded and 116 had biopsy. 14 were suspected MPM, 10 of whose biopsies were implanted into mice, and 5 were confirmed as mesothelioma. 2 PDX models succeeded, one from a 55-year-old male and one from an 85-year-old female. For each model, tumors were transplanted into 10 mice, with 7 untreated control mice; 6 of 10 PDX1 mice and 8 of 10 PDX2 mice grew tumors used for metabolomics.
• Exposure: Asbestos exposure was not studied. The two patients whose tumors formed the models were recorded in Table 1 as having no asbestos exposure. The experimental exposure was implantation of patient tumor tissue into immunodeficient BALB/c mice.
• Main results:
  • Of 10 implanted biopsies, 5 were pathologically confirmed as mesothelioma. Of these 5, 3 failed to grow on mice from P0 to P2 and 2 models were successfully constructed.
  • Staining showed epithelioid features (PDX1, from the 55-year-old male) and sarcomatoid features (PDX2, from the 85-year-old female) of MPM in both the primary tumors and the mouse tumors.
  • 209 metabolites were annotated in mouse serum. In PDX1 versus control mice, 58 metabolites were upregulated and 23 downregulated.
  • In PDX2 versus control mice, 21 metabolites were upregulated and 3 downregulated. Unsupervised PCA separated PDX1 from controls but could not separate PDX2 from controls.
  • Kynurenine was upregulated in PDX1 and also significantly upregulated in PDX2, with a fold change of 1.99 compared to controls.
  • Succinic acid increased 2.17-fold in PDX1 and 1.49-fold in PDX2. Pyruvic acid increased 1.40-fold in PDX1 and 1.37-fold in PDX2. Lactic acid was upregulated in PDX2 but not in PDX1.
  • Uric acid, uridine and inosine were significantly upregulated in both PDX1 and PDX2 compared with controls.
• The authors' conclusion: The authors concluded that they had developed a modeling technique to facilitate malignant mesothelioma research, especially in China, by easing sample scarcity. They also concluded that studies with larger sample sizes, and further investigation of molecular mechanisms and genetic predispositions, are needed to verify the results.
• Limitations the authors state:
  • The changed metabolites were only phenotypes, without clear molecular mechanisms.
  • Genetic mutation information was available for only one patient, so differences by BAP1 status could not be compared.
  • Studies with larger sample sizes are needed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Carcinoma, Pleural Cavity, Biomarker, Prognosis, Misdiagnosis, Pleural Thickening, Ultrasound.

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