Project description:We analysed the molecular effects on gene modulation exerted by inhibition of miRNA 503 expression in mesothelioma. In vitro results demonstrated that its inhibition determined apoptosis and reduced cancer properties in two different mesothelioma cell lines including one resistant to conventional chemotherapeutic treatment.
Project description:We analysed the molecular effects on gene modulation exerted by aglianico grape seed extract (AGS) in mesothelioma. Previous results allowed to demonstrate that AGS polar extracts determined apoptosis in three different mesothelioma cell lines including one resistant to conventional chemotherapeutic treatment. In addition this treatment affected tumorigenic and invasive properties of these cells We used microarrays to identify molecular pathway deregulated by AGS treatment and involved in apoptosis induction.
Project description:Targeted spatial transcriptomic profiling was performed on seven formalin-fixed paraffin-embedded pleural mesothelioma tumor samples from four cases using the 10x Genomics Xenium platform. The Xenium Human Immuno-Oncology panel supplemented with 100 additional custom genes selected from known pleural mesothelioma biomarkers and single-cell RNA-seq-derived marker genes was used. Raw and processed Xenium files are provided for each sample. To ensure data integrity with downloaded Xenium files, md5 checksums are provided in 'Xenium_GEO.md5'. This dataset is part of a multi-modality study including matched scRNA-seq, bulk RNA-seq, and Xenium spatial transcriptomics generated from overlapping pleural mesothelioma samples. Related controlled-access sequencing data are available in dbGaP under accession phs004285.
Project description:More than half of malignant mesothelioma patients show alterations in the BAP1 tumour suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome which may create new vulnerabilities that remain largely unknown. Here we performed a CRISPR/Cas9-kinome screen in mesothelioma cells that identified two kinases in the Mevalonate/Cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression and genetic perturbation data in mesothelioma cells suggests a dependency on Polycomb repressive complex 2 (PRC2) mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (Zoledronic Acid) and PRC2 inhibition (Tazemetostat), we demonstrate a potent anti-tumour effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma
Project description:Malignant pleural mesothelioma (MPM) is a rare thoracic cancer associated with poor prognosis and low survival rates. In solid cancers, repurposed dopamine receptor antagonists have been shown to have anti-cancer effects. Moreover, in combination with radiotherapy, quetiapine (QTP), a dopamine (D) 2/3 receptor antagonist, has been shown to interfere with self-renewal capacity in glioma-initiating cells and increase survival in mouse models of glioblastoma. In this study we explore combined treatment effects in MPM. Using mesothelioma cell lines, MSTO-211H, H2052, and H2452, and MSTO-211H-derived orthotopic xenograft mouse model of MPM we examined how QTP combined with radiation affects mesothelioma-initiating cells (MICs) in vitro and survival in vivo. Subsequently, bulk and single cell RNA sequencing was used to characterize the transcriptomic landscape of MSTO-211H treated with combined radiation and QTP. We demonstrate that combining QTP with radiation reduces MIC self-renewal capacity and stem cell frequency. In vivo, this combination therapy significantly extends the median survival of mesothelioma-bearing mice. Clonogenic survival assays revealed that QTP does not enhance radiosensitivity in the tested mesothelioma cell lines. Sequencing data revealed, combined treatment upregulated genes involved in cholesterol homeostasis, depleted cancer stem cells, and increased cellular senescence. Taken together, our study highlights the therapeutic potential of radiation with QTP in the treatment of MPM.
Project description:Malignant pleural mesothelioma (MPM) is a rare thoracic cancer associated with poor prognosis and low survival rates. In solid cancers, repurposed dopamine receptor antagonists have been shown to have anti-cancer effects. Moreover, in combination with radiotherapy, quetiapine (QTP), a dopamine (D) 2/3 receptor antagonist, has been shown to interfere with self-renewal capacity in glioma-initiating cells and increase survival in mouse models of glioblastoma. In this study we explore combined treatment effects in MPM. Using mesothelioma cell lines, MSTO-211H, H2052, and H2452, and MSTO-211H-derived orthotopic xenograft mouse model of MPM we examined how QTP combined with radiation affects mesothelioma-initiating cells (MICs) in vitro and survival in vivo. Subsequently, bulk and single cell RNA sequencing was used to characterize the transcriptomic landscape of MSTO-211H treated with combined radiation and QTP. We demonstrate that combining QTP with radiation reduces MIC self-renewal capacity and stem cell frequency. In vivo, this combination therapy significantly extends the median survival of mesothelioma-bearing mice. Clonogenic survival assays revealed that QTP does not enhance radiosensitivity in the tested mesothelioma cell lines. Sequencing data revealed, combined treatment upregulated genes involved in cholesterol homeostasis, depleted cancer stem cells, and increased cellular senescence. Taken together, our study highlights the therapeutic potential of radiation with QTP in the treatment of MPM.
Project description:Desmoplastic malignant mesothelioma is a rare tumor. Due to the rarity, genomic profile of desmoplastic malignant mesothelioma is not unveiled. To elucidate genomic profile of desmoplastic malignant mesothelioma, we used illumina infinium omini exomeexpress in an established patient-derived cell line of desmoplastic malignant mesothelioma.