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

SIMPLE SUMMARY: Malignant pleural mesothelioma (MPM) is a rare tumor with unfavorable prognosis for which new therapeutic interventions are urgently needed. The aim of our study was to develop a preclinical model representative of the different histotypes found in human tumors that can be used as models for the discovery of new treatments and combinations. We successfully generated patient-derived xenografts (PDXs) from MPM, which strongly resembled the tumors of origin in terms of morphology and immunohistochemistry. These tumors, when growing in mice, poorly respond to cisplatin, a finding that aligned with the clinical results. From one of the PDXs, we generated 2D and 3D cultures maintaining the phenotypical characteristics of human tumors and PDXs. Altogether, these preclinical models represent a useful tool for the discovery of new targets and drug combinations. 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.