Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

Jean, Didier; Jaurand, Marie‐Claude

doi:10.3390/ijms19082191

Cited by 10 publications

(9 citation statements)

References 73 publications

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“…A few genetic models of MM have previously been reported based on the inactivation of Nf2, Bap1, Ink4a/Arf, Trp53, Tsc1, and Pten-with or without the combined administration of asbestos. In most cases, the three major histologic subtypes of MM developed but only Nf2;Rb and Pten;Trp53 combined genetic loss leads to exclusively nonepithelioid (17,19,35). In our hands, adenovirus-Cre-mediated Pten;Trp53 inactivation resulted in SMM development with a median latency and histology similar to those reported by Sementino and colleagues, but we did not observe biphasic MM, as they did.…”

Section: Discussionsupporting

confidence: 88%

Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

et al. 2020

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Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gai2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110b/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110b/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gai2 expression levels as predictive markers of response to combined MEK and p110b/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking.Significance: Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.

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Section: Discussionsupporting

confidence: 88%

Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

et al. 2020

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“…In this system, the rate of MPM is dependent on the type of inactivated genes; high rates occur with at least two hom genes, including Trp53. Survival generally exceeds 30-50 weeks, although shorter survivals occur in a few situations with hom/hom combinations (70). Similar results were recently reported by inactivating Ink4a, Nf2, and Bap1 (71).…”

Section: In Vivo Modelssupporting

confidence: 86%

“…With regard to conditional mutant mice, it takes several months to more than 1 year before the development of a MM. While the morphological features are reproduced, the sarcomatoid MM subtype most frequently forms, contrary to what is observed in humans (70).…”

Section: In Vivo Modelsmentioning

confidence: 62%

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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“…It is postulated that activation of the NLRP3 inflammasome may play a role in the pathogenesis of mesothelioma [ 58 ]. Other involved molecular events were reviewed by [ 59 ].…”

Section: Nm and The Thoracic Cavitymentioning

confidence: 99%

Nanomaterials and the Serosal Immune System in the Thoracic and Peritoneal Cavities

Kuper¹,

Pieters

Bilsen

2021

IJMS

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The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune system. Innate lymphoid cells (ILCs) are found abundantly in the thoracic and peritoneal cavities, and they are crucial in first defense against pathogenic viruses and bacteria. Nanomaterials (NMs) can enter the cavities intentionally for medical purposes, or unintentionally following environmental exposure; subsequent serosal inflammation and cancer (mesothelioma) has gained significant interest. However, reports on adverse effects of NM on ILCs and other components of the serosal immune system are scarce or even lacking. As ILCs are crucial in the first defense against pathogenic viruses and bacteria, it is possible that serosal exposure to NM may lead to a reduced resistance against pathogens. Additionally, affected serosal lymphoid tissues and cells may disturb adipose tissue homeostasis. This review aims to provide insight into key effects of NM on the serosal immune system.

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Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

Cited by 10 publications

References 73 publications

Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

Nanomaterials and the Serosal Immune System in the Thoracic and Peritoneal Cavities

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