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Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

ABSTRACT: BACKGROUND:Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options. METHODS:We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples. FINDINGS:A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series. INTERPRETATION:The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.

SUBMITTER: Alcala N

PROVIDER: S-EPMC6838392 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

Alcala Nicolas N Mangiante Lise L Le-Stang Nolwenn N Gustafson Corinne E CE Boyault Sandrine S Damiola Francesca F Alcala Karine K Brevet Marie M Thivolet-Bejui Françoise F Blanc-Fournier Cécile C Le Rochais Jean-Philippe JP Planchard Gaëtane G Rousseau Nathalie N Damotte Diane D Pairon Jean Claude JC Copin Marie Christine MC Scherpereel Arnaud A Wasielewski Eric E Wicquart Laurence L Lacomme Stéphanie S Vignaud Jean-Michel JM Ancelin Gaspard G Girard Cécile C Sagan Christine C Bonnetaud Christelle C Hofman Véronique V Hofman Paul P Mouroux Jérôme J Thomas de Montpreville Vincent V Clermont-Taranchon Estelle E Mazieres Julien J Rouquette Isabelle I Begueret Hugues H Blay Jean-Yves JY Lantuejoul Sylvie S Bueno Raphael R Caux Christophe C Girard Nicolas N McKay James D JD Foll Matthieu M Galateau-Salle Françoise F Fernandez-Cuesta Lynnette L

EBioMedicine 20191021

<h4>Background</h4>Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options.<h4>Methods</h4>We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples.<h4>Findings</h4>A continuum of molecular profiles explained the pr ...[more]

PMID: 31648983

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Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.

Project description:Malignant pleural mesothelioma (MPM) is an aggressive cancer affecting the outer lining of the lung, with a median survival of less than one year. We constructed an 'MPM interactome' with over 300 computationally predicted protein-protein interactions (PPIs) and over 2400 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from Biological General Repository for Interaction Datasets (BioGRID) and Human Protein Reference Database (HPRD). Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, and gene expression in microarray experiments, and classifies the pairwise features as interacting or non-interacting based on a random forest model. We validated five novel predicted PPIs experimentally. The interactome is significantly enriched with genes differentially ex-pressed in MPM tumors compared with normal pleura and with other thoracic tumors, genes whose high expression has been correlated with unfavorable prognosis in lung cancer, genes differentially expressed on crocidolite exposure, and exosome-derived proteins identified from malignant mesothelioma cell lines. 28 of the interactors of MPM proteins are targets of 147 U.S. Food and Drug Administration (FDA)-approved drugs. By comparing disease-associated versus drug-induced differential expression profiles, we identified five potentially repurposable drugs, namely cabazitaxel, primaquine, pyrimethamine, trimethoprim and gliclazide. Preclinical studies may be con-ducted in vitro to validate these computational results. Interactome analysis of disease-associated genes is a powerful approach with high translational impact. It shows how MPM-associated genes identified by various high throughput studies are functionally linked, leading to clinically translatable results such as repurposed drugs. The PPIs are made available on a webserver with interactive user interface, visualization and advanced search capabilities.

Dataset Information

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

Publications

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

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