Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability

Our plain-English summary of Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability, by Y. Song, S.S. Baxter, L. Dai, et al (Cancers, 2022).

The study

• Authors: Y. Song, S.S. Baxter, L. Dai, C. Sanders, S. Burkett, R.N. Baugher, S.D. Mellott, T.B. Young, H.E. Lawhorn, S. Difilippantonio, B. Karim, Y. Kadariya, L.A. Pinto, J.R. Testa, R.H. Shoemaker
• Journal: Cancers
• Published: 2022;14(13)
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe are mutations in tumor suppressor genes. Several genetically engineered mouse models have been generated by introducing the same genetic lesions found in human MMe. However, most of these models require specialized breeding facilities and long-term exposure of mice to asbestos for MMe development. Thus, an alternative model with high tumor penetrance without asbestos is urgently needed. We characterized an orthotopic model using MMe cells derived from Cdkn2a+/-;Nf2+/- mice chronically injected with asbestos. These MMe cells were tumorigenic upon intraperitoneal injection. Moreover, MMe cells showed mixed chromosome and microsatellite instability, supporting the notion that genomic instability is relevant in MMe pathogenesis. In addition, microsatellite markers were detectable in the plasma of tumor-bearing mice, indicating a potential use for early cancer detection and monitoring the effects of interventions. This orthotopic model with rapid development of MMe without asbestos exposure represents genomic instability and specific molecular targets for therapeutic or preventive interventions to enable preclinical proof of concept for the intervention in an immunocompetent setting.

In plain English

This laboratory study characterized six murine malignant mesothelioma (MMe) cell lines derived from ascitic fluid and/or peritoneal lavage of asbestos-injected, tumor-bearing Cdkn2a+/-;Nf2+/- mice on an FVB/NCrl background, and used them to build an orthotopic mouse model. All six lines expressed mesothelin and WT1 by immunohistochemistry, and all were tumorigenic after intraperitoneal injection into syngeneic FVB/NCrl mice (10 per group), though take rates varied: 100% for MM201, MM96, MM87 (1 x 10^7) and MM58, 80% for MM410 and 30% for MM380. Median survival was 23 days post inoculation for MM58 and 27 for MM87, versus 68 for MM201 and 101 for MM96. Subcutaneous injection of MM96 did not reach a 100% take rate by 114 dpi. Spectral karyotyping showed polysomy and translocations in all six lines, and two of six microsatellite loci (mBat64, mBat67) showed deletions in MM201, MM87 and MM410; the same microsatellite profile was detected in plasma cell-free DNA of tumor-bearing mice.

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: experimental laboratory study in mice: characterization of six murine mesothelioma cell lines plus syngeneic tumorigenicity (intraperitoneal and subcutaneous) experiments and genomic analyses
• Who was studied: Six MMe cell lines (MM58, MM87, MM96, MM201, MM380, MM410) from asbestos-injected Cdkn2a+/-;Nf2+/- mice, and female or male FVB/NCrl recipient mice aged 7-8 weeks, 10 per group, at NCI-Frederick (animal protocol approved 19 January 2016)
• Exposure: No new asbestos exposure in this study; the cell lines came from asbestos-induced peritoneal mesotheliomas in Cdkn2a+/-;Nf2+/- mice, and recipient mice received injections of cultured tumour cells only
• Main results:
  • After intraperitoneal injection, take rates were 100% for MM201, MM96, MM87 (1 x 10^7) and MM58, 80% for MM410 (5 x 10^6) and 30% for MM380 (1 x 10^7)
  • Median survival after intraperitoneal injection was 23 days post inoculation for MM58 and 27 for MM87, compared with 68 for MM201 and 101 for MM96
  • Subcutaneous injection of MM96 (up to 5 x 10^6 cells) did not reach a 100% take rate by 114 dpi, and those tumours had a very low proliferation rate
  • Spectral karyotyping showed chromosomal abnormalities, polysomy and translocations in all six cell lines
  • In MM201, MM87 and MM410, two of six microsatellite markers showed deletions; mBat64 showed a deletion of 43 As and Sanger sequencing confirmed a 258 bp deletion around mBat67
  • The same microsatellite instability profile was found in plasma cell-free DNA of mice inoculated with MM58, MM410 and MM201 cells
  • All six cell lines expressed mesothelin (highest by flow cytometry in MM96, 94.1%), with strong staining on immunohistochemistry
• The authors' conclusion: The authors concluded that they established a syngeneic orthotopic model from asbestos-induced Cdkn2a+/-;Nf2+/- mesothelioma cells, that these cells showed a mixed state of chromosome and microsatellite instability, and that the model offers molecular targets for preclinical testing without needing adenovirus or asbestos injection
• Limitations the authors state:
  • The authors noted that therapeutic activity in a mouse model does not necessarily predict human response, and no preclinical model has absolute predictive value
  • The authors noted the model recapitulates only a subset of mesothelioma because only Cdkn2a and Nf2 were manipulated
  • The authors noted it is difficult to monitor response to an intervention in an intraperitoneal tumour model
  • The authors stated that further studies are needed to determine the mechanism of the microsatellite instability seen in these cells

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Microsatellite Instability (MSI-H), Malignant Mesothelioma, Pericardial, Carcinogenic, Mineral Fiber, Tumor Suppressor Gene, CDKN2A.

Related studies

• Mismatch Repair Protein Defects and Microsatellite Instability in Malignant Pleural Mesothelioma — S. Arulananda, B. Thapa, et al. (2018)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)
• Genomic changes of chromosomes 8p23.1 and 1q21: Novel mutations in malignant mesothelioma — G. Serio, L. Vimercati, et al. (2018)
• Genomic profiling of the genes on chromosome 3p in sporadic clear cell renal cell carcinoma — Y. Togo, Y. Yoshikawa, et al. (2016)
• A mouse model recapitulating molecular features of human mesothelioma — D.A. Altomare, C.A. Vaslet, et al. (2005)
• Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model — J.M. Hillegass, A. Shukla, et al. (2010)

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