Preclinical Models and Resources to Facilitate Basic Science Research on Malignant Mesothelioma – A Review

Abstract

Malignant mesothelioma is an aggressive cancer with poor prognosis, predominantly caused by human occupational exposure to asbestos. The global incidence of mesothelioma is predicted to increase as a consequence of continued exposure to asbestos from a variety of sources, including construction material produced in the past in developed countries, as well as those currently being produced in developing countries. Mesothelioma typically develops after a long latency period and consequently it is often diagnosed in the clinic at an advanced stage, at which point standard care of treatment, such as chemo- and radio-therapy, are largely ineffective. Much of our current understanding of mesothelioma biology, particularly in relation to disease pathogenesis, diagnosis and treatment, can be attributed to decades of preclinical basic science research. Given the postulated rising incidence in mesothelioma cases and the limitations of current diagnostic and treatment options, continued preclinical research into mesothelioma is urgently needed. The ever-evolving landscape of preclinical models and laboratory technology available to researchers have made it possible to study human disease with greater precision and at an accelerated rate. In this review article we provide an overview of the various resources that can be exploited to facilitate an enhanced understanding of mesothelioma biology and their applications to research aimed to improve the diagnosis and treatment of mesothelioma. These resources include cell lines, animal models, mesothelioma-specific biobanks and modern laboratory techniques/technologies. Given that different preclinical models and laboratory technologies have varying limitations and applications, they must be selected carefully with respect to the intended objectives of the experiments. This review therefore aims to provide a comprehensive overview of the various preclinical models and technologies with respect to their advantages and limitations. Finally, we will detail about a highly valuable preclinical laboratory resource to curate high quality mesothelioma biospecimens for research; the biobank. Collectively, these resources are essential to the continued advancement of precision medicine to curtail the increasing health burden caused by malignant mesothelioma.

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

“…For cancer research, these include cell lines, 3D organoids, or systems in living organisms, in particular rodents (summarized in [4]). Syngeneic mouse models with subcutaneously injected cell lines are widely used due to the reproducible tumor take, visible tumor formation, and the fact that they have been extensively used to test new treatments for MPM (summarized in [5]).…”

Molecular Alterations in Malignant Pleural Mesothelioma: A Hope for Effective Treatment by Targeting YAP

“…Over the past 20 years, the morphological analysis of the three histological subtypes, including epithelioid, biphasic also called mixed, and sarcomatoid forms, has been the primary indicator for therapeutic decision making at an advanced disease stage [5,19,20]. In daily practice, only a few effective biomarkers have been recommended for MPM [21], whereas an invasive biopsy followed by first-line systematic chemotherapy with cisplatin plus pemetrexed, with or without bevacizumab, are still the main treatment options [22][23][24]. Indeed, double immunotherapy combining nivolumab and ipilimumab has recently emerged for frontline [25] or second-line therapy [26], with an overall survival (OS) benefit that was mainly observed in patients with the non-epithelioid histological subtype, while median OS in patients with the epithelioid subtype was close to that recorded in patients who underwent chemotherapy plus bevacizumab (around 18 months) [21].…”

Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library

“…A major challenge to identifying effective treatments has been the relative lack of model systems that accurately reflect DPM tumorigenesis. Researchers are heavily reliant on the established commercially available DPM cell lines, which have inherent limitations including concerns for discordant molecular findings from the parental tumor possibly secondary to in vitro clonal expansion [14][15][16][17]. Patient-derived xenografts (PDXs) have emerged as valuable tools to interrogate the genomic landscape of cancers.…”

“…The ability to link phenotypes observed in PDXs to those of individual patients, including correlation with clinical response to therapy, may make them a particularly valuable tool for DPM biologic and therapeutic research. A review of the literature shows a moderate number of murine models established in DPM, some of which are genetically engineered; of the patient derived models, there is limited in-depth analyses of the mutational and gene expression landscape of these models confirming their resemblance to the parental tumor samples [17][18][19][20][21].…”