Project description:Malignant pleural mesothelioma (MPM), which is associated with occupational asbestos exposure, is a deadly disease with no effective treatments due mainly to its high resistance to anti-cancer drugs. The molecular mechanisms responsible for its chemotherapeutic resistance are complicated and undefined. However, the presence of side population cells (SP cells) in tumors is a well-accepted explanation for their anti-cancer drug resistance. To identify SP cell-specific gene expression signature, microarray technique has been employed. Our data show differential gene expression profiles between SP and non-SP cells of H2714 mesothelioma cells. SP cells over-expressed genes associated with cancer stem cell (CSC) and drug resistance: DUSP6, SPRY2 and IL6, as well as multi-pathways, including the cancer stem cell-associated pathways Notch and c-Kit. Therefore, we believe that targeting CSC-specific genes and pathways in SP cells may hold the key to the discovery of effective treatments for reversing chemotherapeutic resistance to MPM treatment. 4 samples
Project description:Malignant pleural mesothelioma (MPM), which is associated with occupational asbestos exposure, is a deadly disease with no effective treatments due mainly to its high resistance to anti-cancer drugs. The molecular mechanisms responsible for its chemotherapeutic resistance are complicated and undefined. However, the presence of side population cells (SP cells) in tumors is a well-accepted explanation for their anti-cancer drug resistance. To identify SP cell-specific gene expression signature, microarray technique has been employed. Our data show differential gene expression profiles between SP and non-SP cells of H2714 mesothelioma cells. SP cells over-expressed genes associated with cancer stem cell (CSC) and drug resistance: DUSP6, SPRY2 and IL6, as well as multi-pathways, including the cancer stem cell-associated pathways Notch and c-Kit. Therefore, we believe that targeting CSC-specific genes and pathways in SP cells may hold the key to the discovery of effective treatments for reversing chemotherapeutic resistance to MPM treatment.
Project description:Regional delivery of oncolytic viruses has been shown to promote immune responses. Malignant pleural effusions comprise an immunosuppressive microenvironment, and the ability of oncolytic viruses to generate immune responses following regional delivery in patients with malignant pleural effusions is unknown. We conducted a phase I clinical trial that studied the intrapleural administration of oncolytic vaccinia virus to establish the safety and feasibility in patients with malignant pleural effusion due to malignant pleural mesothelioma or metastatic disease. In patients with malignant pleural mesothelioma, by correlative analysis of pre- and post-treatment tumor biopsies, we provide insight into tumor-specific viral uptake and associated immune responses.
Project description:We screened pleural effusion proteomes of mesothelioma and lung adenocarcinoma patients to identify novel soluble mesothelioma biomarkers. We performed quantitative mass spectrometry-(MS-) based proteomics using isobaric tags for relative and absolute quantification (iTRAQ) and used narrow range immobilized pH gradient/high resolution isoelectric focusing (IPG/HiRIEF; pH 4 to 4.25) prior to analysis by nano liquid chromatography-coupled MS/MS. Pleural effusions from patients with malignant mesothelioma (n=6), lung adenocarcinoma (n=6), or benign mesotheliosis (n=7) were analyzed, and more than 1,300 proteins were identified.
Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, downregulation of YAP1 by shRNA results in modulation of YAP1/TEAD-dependent gene expression and regression of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, YAP1 activity is essential to maintain the growth of mesothelioma cells in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.
Project description:Diagnosis of malignant pleural mesothelioma (MPM) is difficult, the most common differential diagnosis being benign pleural diseases and metastatic adenocarcinomas. In order to identify novel markers able to improve diagnostic accuracy, we performed a genome-wide gene expression analysis on tumor cells lines established from pleural effusions (13 MPM and 4 lung adenocarcinoma). Our microarray analysis led to the identification of genes encoding novel cellular and soluble markers whose expression was validated by RT-qPCR. Immunohistochemical staining of tumor biopsies with anti-type-III collagen antibodies were positive in mesothelioma cells but not in adenocarcinoma cells. Using ELISA, we showed that the C-C motif chemokine 2 (CCL2) concentration was significantly higher in pleural effusions from patients with mesothelioma (n = 61) than in subjects with adenocarcinoma (n = 25) or with benign pleural effusions (n = 15): median (interquartile range) = 2.99 ng/mL (1.76-6.01) versus 0.99 ng/mL (0.51-1.83) and 1.47 ng/mL (0.80-1.56), respectively, P < 0.0001. Conversely, the galectin-3 concentration was lower in mesothelioma: 11.50 ng/mL (6.73-23.53) versus 24.74 ng/mL (20.42-70.35) and 17.64 ng/mL (14.81-24.68), respectively, P < 0.0001. The AUC for CCL2 were 0.8030 and 0.7716 for differentiating mesothelioma from adenocarcinoma or benign effusions, respectively. Similarly, the AUC obtained for galectin-3 were 0.7980 and 0.6923, respectively. In conclusion, type-III collagen, CCL2 and galectin-3 are promising new diagnostic markers for mesothelioma.