scholarly journals BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma

2020 ◽  
Author(s):  
Y Ishii ◽  
KK Kolluri ◽  
A Pennycuick ◽  
E Nigro ◽  
D Alrifai ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Regulation Of Gene Expression ◽  
Inverse Correlation ◽  
Death Receptors ◽  
Tumour Suppressor Gene ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
Incurable Cancer ◽  
Trail Receptors ◽  
Frequent Event

AbstractMalignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the lungs with few treatment options. We recently reported loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptors 4 (DR4) and 5 (DR5). Using tissue microarray (TMAs) of tumour samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptors. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wild-type BAP1, but not catalytically-inactive mutant BAP1, reduced promoter activities of DR4 and DR5, suggesting deubiquinase activity plays an important role in the regulation of gene expression. Co-IP studies demonstrated direct binding of BAP1 and the transcription factor Ying Yang 1 (YY1) and ChIP assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Notably, shRNA knockdown of YY1 also increased DR4 and DR5 expression, and sensitivity to TRAIL. These results demonstrate that BAP1 and YY1 together negatively regulate transcriptional activity of TRAIL receptors. BAP1 and YY1 may both therefore be strong therapeutic targets to enhance the efficacy of TRAIL-induced apoptosis.Statement of significanceWe describe how the most-frequently mutated tumour suppressor gene in mesothelioma regulates the response to TNF-related apoptosis-inducing ligand (TRAIL). These findings will accelerate a biomarker-driven cancer therapy.

scholarly journals BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma

2021 ◽  
pp. 101223
Author(s):  
Yuki Ishii ◽  
Krishna K. Kolluri ◽  
Adam Pennycuick ◽  
Xidan Zhang ◽  
Ersilia Nigro ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Death Receptors ◽  
Pleural Mesothelioma

scholarly journals Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM)

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 7
Author(s):  
Moshe Lapidot ◽  
Abigail E. Case ◽  
Dalia Larios ◽  
Helen I. Gandler ◽  
Chengcheng Meng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transcription Factor ◽  
Cell Growth ◽  
Malignant Pleural Mesothelioma ◽  
Cell Cycle Progression ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
P53 Response

Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2). Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.

scholarly journals Photodynamic Therapy for Malignant Pleural Mesothelioma

2012 ◽  
Vol 10 (Suppl_2) ◽  
pp. S-75-S-79 ◽  
Author(s):  
Joseph S. Friedberg
Keyword(s):  
Quality Of Life ◽  
Immune Response ◽  
Photodynamic Therapy ◽  
Malignant Pleural Mesothelioma ◽  
Surgical Procedures ◽  
Multimodal Treatment ◽  
Pleural Mesothelioma ◽  
Collaborative Effort ◽  
Incurable Cancer

Surgery is the treatment option most likely to be associated with prolonged remission in patients with malignant pleural mesothelioma. However, it remains investigational and must always be combined with other modalities to treat the microscopic disease that remains after the most aggressive operations. Improvements in quality of life for appropriate patients with this rare yet incurable cancer may be obtained with less drastic lung-sparing surgical procedures along with intraoperative use of photodynamic therapy (PDT). Very encouraging survival results have been obtained with the combination of surgery and PDT, which requires the well-orchestrated collaborative effort of an extensive team of professionals, from thoracic surgeons and radiation oncologists to basic science researchers. Multi-institutional trials are necessary to duplicate these early findings and shed more light on the tumor-directed immune response of this surgically based multimodal treatment.

scholarly journals Metabolic rewiring and redox alterations in malignant pleural mesothelioma

2019 ◽  
Vol 122 (1) ◽  
pp. 52-61 ◽  
Author(s):  
Loredana Urso ◽  
Ilaria Cavallari ◽  
Evgeniya Sharova ◽  
Francesco Ciccarese ◽  
Giulia Pasello ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Malignant Pleural Mesothelioma ◽  
Tumour Progression ◽  
Mesothelial Cells ◽  
Polyamine Metabolism ◽  
Aetiological Factor ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
Control Of Gene Expression ◽  
Dismal Prognosis

AbstractMalignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in 18F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.

scholarly journals MicroRNA Signatures in Malignant Pleural Mesothelioma Effusions

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Kimberly A. Birnie ◽  
Cecilia M. Prêle ◽  
Arthur W. (Bill) Musk ◽  
Nicholas de Klerk ◽  
Y. C. Gary Lee ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Malignant Pleural Mesothelioma ◽  
Area Under The Curve ◽  
Stable Expression ◽  
Pleural Mesothelioma ◽  
Incurable Cancer

Malignant pleural mesothelioma (MPM) is an incurable cancer of the pleura that can be difficult to diagnose. Biomarkers for an easier and/or earlier diagnosis are needed. Approximately 90% of MPM patients develop a pleural effusion (PE). PEs are ideal sources of biomarkers as the fluid would almost always require drainage for diagnostic and/or therapeutic reasons. However, differentiating MPM PE from PE caused by other diseases can be challenging. MicroRNAs are popular biomarkers given their stable expression in tissue and fluid. MicroRNAs have been analysed in PE cytology samples for the diagnosis of MPM but have not been measured in frozen/fresh PE. We hypothesise that microRNAs expressed in PE are biomarkers for MPM. TaqMan OpenArray was used to analyse over 700 microRNAs in PE cells and supernatants from 26 MPMs and 21 other PE-causing diseases. In PE cells, combining miR-143, miR-210, and miR-200c could differentiate MPM with an area under the curve (AUC) of 0.92. The three-microRNA signature could also discriminate MPM from a further 40 adenocarcinomas with an AUC of 0.9887. These results suggest that the expression of miR-143, miR-210, and miR-200c in PE cells might provide a signature for diagnosing MPM.

scholarly journals KRAS signalling in malignant pleural mesothelioma

2020 ◽  
Author(s):  
Antonia Marazioti ◽  
Christophe Blanquart ◽  
Anthi C. Krontira ◽  
Mario A. A. Pepe ◽  
Caroline M. Hackl ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Pleural Cavity ◽  
Expression Profiles ◽  
Significant Proportion ◽  
Ectopic Expression ◽  
Point Mutations ◽  
Gene Expression Profiles ◽  
Pleural Mesothelioma ◽  
Copy Number Alterations ◽  
Loss Of Function

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to the development of pleural effusion and death. MPM harbours loss-of-function mutations in genes like BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here we show that a significant proportion of human MPM harbour point mutations and copy number alterations in the KRAS proto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS mutations likely play an important and underestimated role in MPM, which warrants further exploration.

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