Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications

Suraokar, Milind; Núñez, Manuel; Diao, Lixia; Chow, C. W.; Kim, D.; Behrens, Carsten; Lin, Hua; Lee, S.; Raso, Gabriela; Moran, Chelsea; Rice, David W.; Mehran, Reza J.; Lee, J. J.; Pass, Harvey I.; Wang, J.; Momin, Amin A.; James, Brian P.; Corvalán, Alejandro; Coombes, Kevin R.; Tsao, Anne S.; Wistuba, Ignacio I.

doi:10.1093/annonc/mdu127

Cited by 52 publications

(60 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the context of previous studies investigating novel tumour-derived biomarkers for MM, Suraokar et al 87. reported gene expression microarray profiling (global transcriptomic microarray analysis) of 53 surgically resected MMs tumours along with paired normal tissue.…”

Section: Resultsmentioning

confidence: 99%

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Greening

Chen

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets.

show abstract

Section: Resultsmentioning

confidence: 99%

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Greening

Chen

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Histone Western blots were conducted with 3–5 μg of histones. For Histone LC/MS, 12 million control and Bap1 KO cells were lysed, nuclei were isolated and histones were extracted using 0.4N H 2 SO 4 and chemically derivatized using propionic anhydride, as previously described 31 . Histones were then digested with trypsin and separated by nano-liquid chromatography (75 μm i.d., 15 cm long, packed with MagicC18aq media, d p 3 μ) coupled to a TSQ Quantum Ultra mass spectrometer.…”

Section: Methodsmentioning

confidence: 99%

Loss of BAP1 function leads to EZH2-dependent transformation

LaFave

Béguelin

Koche

et al. 2015

Nat Med

315

251

View full text Add to dashboard Cite

Introductory Paragraph BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated Ezh2 expression, and enhanced repression of Polycomb Repressive Complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of Bap1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in EZH2 transcriptional regulation, expression of SETD8, the H4K20me1 methyltransferase, reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Further, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.

show abstract

“…Few other genes have already been associated with human mesothelioma such as Lif (Pass et al, 1995). Analysis of pleural mesothelioma compared to matched normal tissue data (Suraokar et al, 2014) revealed that expression of these genes was also increased in human pleural tumors compared to normal tissue, indicating that activation of these developmental pathways is not species specific. Interestingly, one of the genes with the strongest upregulation (p=2.84E-12, FDR=2.05E-11) in tumors compared with crocidolite-exposed tissue was Grem1, a secreted bone morphogenetic protein (BMP) antagonist, which has been recently described to promote epithelial-mesenchymal transition in mesothelioma (Tamminen et al, 2013) ( Figure 6E).…”

Section: Activation Of Developmental Genes Is Predominant In Tumors Wmentioning

confidence: 99%

How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing and somatic mutations

Rehrauer

Blum

et al. 2017

Preprint

View full text Add to dashboard Cite

SummaryChronic exposure to intraperitoneal asbestos triggered a marked response in the mesothelium well before tumor development. Macrophages, mesothelial precursor cells, cytokines and growth factors accumulated in the peritoneal lavage. Transcriptome profiling revealed YAP/TAZ activation in inflamed mesothelium with further activation in tumors, paralleled by increased levels of cells with nuclear YAP/TAZ. Arg1 was one of the highest upregulated genes in inflamed tissue and tumor. Inflamed tissue showed increased levels of single nucleotide variations, with an RNA-editing signature, which were even higher in the tumor samples. Subcutaneous injection of asbestos-treated, but tumor-free mice with syngeneic mesothelioma tumor cells resulted in a significantly higher incidence of tumor growth when compared to naïve mice supporting the role of the environment in tumor progression.

show abstract

Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications

Cited by 52 publications

References 25 publications

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Loss of BAP1 function leads to EZH2-dependent transformation

How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing and somatic mutations

Contact Info

Product

Resources

About