Genomic and Transcriptomic Analyses of Malignant Pleural Mesothelioma (MPM) Samples Reveal Crucial Insights for Preclinical Testing

Our plain-English summary of Genomic and Transcriptomic Analyses of Malignant Pleural Mesothelioma (MPM) Samples Reveal Crucial Insights for Preclinical Testing, by A. Laure, A. Rigutto, M.B. Kirschner, et al (Cancers, 2023).

The study

• Authors: A. Laure, A. Rigutto, M.B. Kirschner, L. Opitz, L. Grob, I. Opitz, E. Felley-Bosco, S. Hiltbrunner, A. Curioni-Fontecedro
• Journal: Cancers
• Published: 2023;15(10)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cell lines are extensively used to study cancer biology. However, the use of highly passaged commercial cell lines has to be questioned, as they do not closely resemble the originating tumor. To understand the reliability of preclinical models for Malignant pleural mesothelioma (MPM) studies, we have performed whole transcriptome and whole exome analyses of fresh frozen MPM tumors and compared them to cell lines generated from these tumors, as well as commercial cell lines and a preclinical MPM mouse model. Patient-derived cell lines were generated from digested fresh tumors and whole exome sequencing was performed on DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor samples, corresponding patient-derived cell lines, and normal tissue. RNA sequencing libraries were prepared from 10 fresh frozen tumor samples, the 10 corresponding patient-derived cell lines, and 7 commercial cell lines. Our results identified alterations in tumor suppressor genes such as FBXW7, CDKN2A, CDKN2B, and MTAP, all known to drive MPM tumorigenesis. Patient-derived cell lines correlate to a high degree with their originating tumor. Gene expressions involved in multiple pathways such as EMT, apoptosis, myogenesis, and angiogenesis are upregulated in tumor samples when compared to patient-derived cell lines; however, they are downregulated in commercial cell lines compared to patient-derived cell lines, indicating significant differences between the two model systems. Our results show that the genome and transcriptome of tumors correlate to a higher degree with patient-derived cell lines rather than commercial cell lines. These results are of major relevance for the scientific community in regard to using cell lines as an appropriate model, resembling the pathway of interest to avoid misleading results for clinical applications.

In plain English

This laboratory study examined malignant pleural mesothelioma (MPM), a cancer of the lining around the lungs. It did not examine asbestos or any other exposure. The authors grew cell lines from tumor tissue of 10 patients having surgery at the University Hospital Zurich between 2018 and 2020. They sequenced the DNA of the tumors and these cell lines. They compared gene activity in the tumors, these patient-derived lines and commercial cell lines (six mesothelioma lines and one non-cancerous control line). They also studied a mouse mesothelioma model called RN5. Five of the ten patient-derived cell lines carried the same mutational changes in tumor genes as their original tumors. For several groups of genes, the patient-derived cell lines resembled the tumors more closely than the commercial cell lines did. The mouse model matched human tumors for some gene groups but not others. The authors concluded that low-passage-number patient-derived cell lines (grown through few rounds of laboratory culture) are a suitable tool for laboratory studies of MPM. They noted that they had few cell lines compared with large patient studies, so their mutation findings were expected to differ from those studies.

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 study. Tumors and the cell lines grown from them underwent DNA sequencing (whole exome). RNA sequencing compared gene activity in tumors, the patient-derived cell lines and commercial cell lines. The study also looked at a mouse model.
• Who was studied: Tumor tissue from 10 patients having surgery before chemotherapy at the University Hospital Zurich, 2018 to 2020. Median age was 66 years (range 64 to 90). Nine patients were male and one female. Seven tumors were epithelioid and three biphasic. The study also used commercial cell lines (MSTO-211, NCI-H28, Mero82, ACC-MESO1, ONE58, ZL55 and the MeT-5A control line) and the murine RN5 model in female C57BL/6 mice.
• Exposure: Not studied. The article reports no asbestos or other exposure information for the patients. It compares types of laboratory model, not exposures.
• Main results:
  • Whole exome sequencing of the 10 patient-derived cell lines and their tumors identified 1339 somatic mutations present in at least one sample. Mutations in 130 genes were present in at least two samples.
  • Deep deletions of chromosome regions containing FBXW7, CDKN2A, CDKN2B and MTAP were found in one patient-derived cell line (MPM693) and its tumor.
  • Five of the 10 patient-derived cell lines had the same mutational changes in tumor genes as their corresponding tumor.
  • On gene-activity analysis, commercial cell lines, patient-derived cell lines and tumors formed three distinct clusters.
  • Gene groups such as EMT, apoptosis, myogenesis and angiogenesis were more active in tumors than in patient-derived cell lines. The same groups were less active in commercial cell lines than in patient-derived cell lines.
  • Class 1 histone deacetylase (HDAC) genes were more active in commercial cell lines than in tumor tissue. The difference between patient-derived cell lines and tumors was not statistically significant.
  • CDKN2A deletions were found in over 80% of commercial cell lines, compared with below 20% of patient-derived cell lines and tumors. The commercial lines here were this study's lines plus others with genomic data from an online database.
  • In the RN5 mouse model, TGF-beta signaling, P53 and hypoxia gene groups followed the same pattern as in human tumors. Reactive oxygen species, PI3K signaling and EMT did not.
  • About 60% of attempts to establish a patient-derived cell line succeeded.
• The authors' conclusion: The authors concluded that low-passage-number patient-derived cell lines are a suitable tool for preclinical studies of MPM, because they closely resemble the genome and transcriptome of the tumors they came from. They added that the choice of mouse model depends on the pathway being studied.
• Limitations the authors state:
  • The authors had few patient-derived cell lines compared with large sequencing studies of MPM patients. They therefore expected the mutation findings in their cell lines and tumors to deviate from those studies. They said the lines still represent different MPM genotypes useful for preclinical work.
  • It remains unclear whether the BAP1 and CDKN2A mutations in commercial cell lines came from the original tumor or arose while the lines were being grown.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tumor Suppressor Gene, CDKN2A, MTAP, Carcinogenesis, Apoptosis, Angiogenesis.

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