Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients

Our plain-English summary of Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients, by R. Affatato, P. Mendogni, A. Del Gobbo, et al (Cancers, 2020).

The study

• Authors: R. Affatato, P. Mendogni, A. Del Gobbo, S. Ferrero, F. Ricci, M. Broggini, L. Rosso
• Journal: Cancers
• Published: 2020;12(12)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a very aggressive tumor originating from mesothelial cells. Although several etiological factors were reported to contribute to MPM onset, environmental exposure to asbestos is certainly a major risk factor. The latency between asbestos (or asbestos-like fibers) exposure and MPM onset is very long. MPM continues to be a tumor with poor prognosis despite the introduction of new therapies including immunotherapy. One of the major problems is the low number of preclinical models able to recapitulate the features of human tumors. This impacts the possible discovery of new treatments and combinations.

Methods: In this work, we aimed to generate patient-derived xenografts (PDXs) from MPM patients covering the three major histotypes (epithelioid, sarcomatoid, and mixed) occurring in the clinic. To do this, we obtained fresh tumors from biopsies or pleurectomies, and samples were subcutaneously implanted in immunodeficient mice within 24 h.

Results: We successfully isolated different PDXs and particularly concentrated our efforts on three covering the three histotypes. The tumors that grew in mice compared well histologically with the tumors of origin, and showed stable growth in mice and a low response to cisplatin, as was observed in the clinic.

Conclusions: These models are helpful in testing new drugs and combinations that, if successful, could rapidly translate to the clinical setting.

In plain English

This laboratory study from Milan, Italy, grew human malignant pleural mesothelioma tumors in mice (patient-derived xenografts) as models for testing drugs. It did not study asbestos exposure. Between March 2017 and May 2020, 29 confirmed mesothelioma samples taken at surgery (17 epithelioid, 7 sarcomatoid, 5 biphasic) were implanted under the skin of immunodeficient mice. Five implants were still under evaluation; of the remaining 24, four became established models (17%, a rate the authors called relatively modest), and three, one per type, were characterized. The mouse tumors resembled the original tumors under the microscope and in marker staining. Their growth rate stayed almost unchanged from the second passage on. Cisplatin shrank none of the three. Treated-to-control tumor size was 104% (sarcomatoid), 61% (biphasic) and 50% (epithelioid), and none fell below the authors' 42% activity threshold. A cell line from the epithelioid model responded poorly to cisplatin and olaparib in flat culture, but olaparib was active when the cells grew as 3D spheres. The authors concluded these models are expected to help discover new treatments and combinations.

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 establishing and characterizing patient-derived xenografts (human tumor implanted in mice), plus cell culture experiments
• Who was studied: 29 malignant pleural mesothelioma samples (17 epithelioid, 7 sarcomatoid, 5 biphasic) from patients who had thoracic surgery at a Milan hospital between March 2017 and May 2020. These came from 35 samples taken from 46 patients operated on; 6 were excluded because final histology did not confirm MPM. Tumors were implanted in female NCr-nu/nu (nude) mice.
• Exposure: No asbestos exposure was studied. In mice, the exposure tested was cisplatin, 5 mg/kg intravenously once a week for three weeks. In the cell line, the drugs tested were cisplatin, olaparib, docetaxel, doxorubicin, BYL-719 and torin-1.
• Main results:
  • Of 29 implants, 5 were still under evaluation. Of the remaining 24, four mouse models were established (two sarcomatoid, one epithelioid, one biphasic), a success rate of 17%. Three were characterized: MESO3 (sarcomatoid), MESO4 (biphasic) and MESO15 (epithelioid).
  • The mouse tumors kept the features of the original patients' tumors under the microscope and in marker staining. The Ki67 proliferation index was nearly the same as in the original tumors, in the range of 40 to 70%.
  • BAP1 and p53 expression matched the original tumors for all samples except BAP1 in MESO 15. That marker was strongly positive in the original tumor and slightly positive in the mouse tumor.
  • From the second passage on, the tumor growth rate remained almost unchanged in all the mouse models.
  • Cisplatin caused no tumor regression in any of the three models (5 mice per group). Treated-to-control tumor weight (T/C%) was 104 at day 49 for MESO3 (sarcomatoid), 61 at day 52 for MESO4 (biphasic) and 50 at day 54 for MESO15 (epithelioid). None reached the activity threshold of below 42.
  • The authors reported that the mouse results matched the patients' clinical course. The patient whose tumor became MESO3 was progressing under cisplatin and died three months after surgery. The MESO15 patient had the longer survival.
  • A cell line could be obtained only from MESO15. In flat (monolayer) culture it responded poorly to cisplatin and olaparib. It responded well to doxorubicin, docetaxel, BYL-719 and torin-1.
  • In MESO15 cells, the concentration halving growth (IC50) for BYL719 was 15 micromolar in flat culture and 7 micromolar in 3D spheres. For olaparib it was greater than 200 micromolar in flat culture and roughly 13 micromolar in 3D.
• The authors' conclusion: The authors concluded that the three models represent the different MPM histotypes and recapitulate the tumors of origin well. They expect the models to be instrumental for discovering new treatments and combinations.
• Limitations the authors state:
  • The success rate was relatively modest (17%). The authors note they used mice lacking T cells but preserving B and NK cells, rather than more severely immunodeficient strains.
  • Because diagnosis had priority, in some cases an adequate specimen for research could not be collected.
  • An immortalized cell line could be obtained only from the epithelioid MESO15 model.

Topics

Medical terms in this study, explained in our Lexicon: Histology, Pleural Mesothelioma, Mesothelial Cells, Environmental Exposure, Latency, Prognosis, Immunotherapy, Discovery.

Related studies

• Establishment and characterization of five human malignant mesothelioma cell lines derived from pleural effusions — L.S. Manning, D. Whitaker, et al. (1991)
• Establishment and characterization of 20 human non-small cell lung cancer cell lines in a serum-free defined medium (ACL-4) — N. Masuda, M. Fukuoka, et al. (1991)
• Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma — M. Wahiduzzaman, S. Karnan, et al. (2019)
• Pre-clinical Models for Malignant Mesothelioma Research: From Chemical-Induced to Patient-Derived Cancer Xenografts — N. Nabavi, J. Wei, et al. (2018)
• Characterization of the bronchoalveolar cellular response in experimental asbestosis. Different reactions depending on the fibrogenic potential — I. Lemaire (1985)
• Management of Asbestos Containing Materials: A Detailed LCA Comparison of Different Scenarios Comprising First Time Asbestos Characterization Factor Proposal — M. Pini, S. Scarpellini, et al. (2021)

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