Heterogeneity in Malignant Pleural Mesothelioma

Oehl, Kathrin; Vrugt, Bart; Opitz, Isabelle; Meerang, Mayura

doi:10.3390/ijms19061603

Cited by 44 publications

(49 citation statements)

References 62 publications

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“…Histological subtypes within these three types have been defined (34). The histological classification only partially captures the tumor heterogeneity observed at both the molecular and clinical levels (35). Large-scale omics and NGS studies have demonstrated MPM heterogeneity at the molecular level that goes beyond the histological classification (14,18,36).…”

Section: Mesothelioma Heterogeneitymentioning

confidence: 99%

“…To better define the polyclonal tumor origin and understand the tumor evolution of mesothelioma, further studies are required in a larger number of tumor samples. Several studies also highlighted the presence of cancer stem cells in MPM (35). In MPM, heterogeneity is not limited to tumor cells; the tumor microenvironment is also distinct from one patient to another in terms of type and number of stromal and immune cells that infiltrate the tumors (43).…”

Section: Mesothelioma Heterogeneitymentioning

confidence: 99%

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The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra-and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.

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Section: Mesothelioma Heterogeneitymentioning

confidence: 99%

Section: Mesothelioma Heterogeneitymentioning

confidence: 99%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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“…MPM displays high heterogeneity, characterized by inter-and intratumor variability at cellular and molecular levels (4,5,126,127). Heterogeneity represents a key mechanism underlying the poor response of MPM patients to current therapeutic interventions and is a challenge in systematic studies aimed at identifying effective treatment and curtailing drug resistance.…”

Section: Further Considerations In Systematic Approachesmentioning

confidence: 99%

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Yang

Schmid

et al. 2020

Front. Oncol.

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Malignant pleural mesothelioma (MPM) is the epitome of a recalcitrant cancer driven by pharmacologically intractable tumor suppressor proteins. A significant but largely unmet challenge in the field is the translation of genetic information on alterations in tumor suppressor genes (TSGs) into effective cancer-specific therapies. The notion that abnormal tumor genome subverts physiological cellular processes, which creates collateral vulnerabilities contextually related to specific genetic alterations, offers a promising strategy to target TSG-driven MPM. Moreover, emerging evidence has increasingly appreciated the therapeutic potential of genetic and pharmacological dependencies acquired en route to cancer development and drug resistance. Here, we review the most recent progress on vulnerabilities co-selected by functional loss of major TSGs and dependencies evolving out of cancer development and resistance to cisplatin based chemotherapy, the only first-line regimen approved by the US Food and Drug Administration (FDA). Finally, we highlight CRISPR-based functional genomics that has emerged as a powerful platform for cancer drug discovery in MPM. The repertoire of MPM-specific "Achilles heel" rises on the horizon, which holds the promise to elucidate therapeutic landscape and may promote precision oncology for MPM.

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“…As well as intertumor heterogeneity, MPM tumors also exhibit intratumor heterogeneity. This tumour complexity limits the ability to delegate suitable treatment options due to the existence of several tumor clones and subclones within a single patient [ 11 ]. Intertumor heterogeneity is inclusive of the variable molecular phenotype of MPM.…”

Section: Introductionmentioning

confidence: 99%

Genomic Deletion of BAP1 and CDKN2A Are Useful Markers for Quality Control of Malignant Pleural Mesothelioma (MPM) Primary Cultures

Sarun

Lee

Williams

et al. 2018

IJMS

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Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of CDNK2A and BAP1 is common in MPM and has potential diagnostic value. Changes in CDKN2A and BAP1 genomic expression were confirmed in MPM samples in the current study using Fluorescence In situ Hybridization (FISH) analysis or copy number variation (CNV) analysis with digital droplet PCR (ddPCR). To determine whether MPM tissue and cell lines were comparable in terms of molecular alterations, IHC marker expression was analyzed in both sample types. The percentage of MPM biomarker levels showed variation between original tissue and matched cells established in culture. Genomic deletions of BAP1 and CDKN2A, however, showed consistent levels between the two. The data from this study suggest that genomic deletion analysis may provide more accurate biomarker options for MPM diagnosis.

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Heterogeneity in Malignant Pleural Mesothelioma

Cited by 44 publications

References 62 publications

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Genomic Deletion of BAP1 and CDKN2A Are Useful Markers for Quality Control of Malignant Pleural Mesothelioma (MPM) Primary Cultures

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