Tumor Suppressor Alterations Cooperate to Drive Aggressive Mesotheliomas with Enriched Cancer Stem Cells via a p53–miR-34a–c-Met Axis

Menges, Craig W.; Kadariya, Yuwaraj; Altomare, Deborah A.; Talarchek, Jacqueline; Neumann-Domer, Erin; Wu, Yue; Xiao, Guang-Hui; Shapiro, Irina M.; Kolev, Vihren N.; Pachter, Jonathan A.; Klein‐Szanto, Andres J.; Testa, Joseph R.

doi:10.1158/0008-5472.can-13-2062

Cited by 53 publications

(64 citation statements)

References 39 publications

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“…In one study, both Nƒ2 and Cdkn2a were HTz [69]. MuMM arose in both WT and Htz mice, more frequently and with a shorter survival in Htz mice than in their WT counterparts, showing the role of these genes in enhancing sensitivity to fibres.…”

Section: Models Of Malignant Mesotheliomamentioning

confidence: 99%

Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

Jean

Jaurand

2018

IJMS

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Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma. Animals were either exposed or not exposed to asbestos or to other carcinogenic fibres, to understand the mechanism of action of fibres at the molecular level, and the role of the selected genes in mesothelial carcinogenesis. The aim of the manuscript was to compare mesothelioma models to human malignant mesothelioma and to specify the clue genes playing a role in mesothelial carcinogenesis. Collectively, MM models recapitulate the clinical features of human MM. At least two altered genes are needed to induce malignant mesothelioma in mice. Two pathways regulated by Cdkn2a and Trp53 seem independent key players in mesothelial carcinogenesis. Other genes and pathways appear as bona fide modulators of the neoplastic transformation.

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Section: Models Of Malignant Mesotheliomamentioning

confidence: 99%

Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

Jean

Jaurand

2018

IJMS

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“…with UICC crocidolite (SPI Supplies) per our usual method (30)(31)(32). Representative examples of scanning electron microscopy (SEM) images of crocidolite fibers, and graphs illustrating fiber length distribution, are depicted in Supplementary Fig.…”

Section: Asbestos Injectionsmentioning

confidence: 99%

Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma

et al. 2014

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Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germlineinactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1 þ/À knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1 þ/À mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1 þ/À mice than in WT animals (median survival, 43 weeks vs. 55weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1 þ/À mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1 þ/À mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1 þ/À mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1 þ/À mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1 þ/À mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure. Cancer Res; 74(16); 4388-97. Ó2014 AACR.

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“…Several studies found cells with CSC properties in MPM (18, 19). Moreover, an elevated CSC population has been demonstrated in a mouse model of aggressive NF2-deficient asbestos-induced mesothelioma (20). FAK plays a role in self-renewal, tumorigenicity and maintenance of mammary CSCs (2).…”

Section: Introductionmentioning

confidence: 99%

Merlin Deficiency Predicts FAK Inhibitor Sensitivity: A Synthetic Lethal Relationship

et al. 2014

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The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition are deficient in the expression of the NF2 tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell-extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlin-negative MPM cells lead to their greater dependence on cell-ECM-induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated ALDH as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response due to reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment.

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Tumor Suppressor Alterations Cooperate to Drive Aggressive Mesotheliomas with Enriched Cancer Stem Cells via a p53–miR-34a–c-Met Axis

Cited by 53 publications

References 39 publications

Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma

Merlin Deficiency Predicts FAK Inhibitor Sensitivity: A Synthetic Lethal Relationship

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