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Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma.

ABSTRACT: Background: Malignant pleural mesothelioma (MPM) is driven by the inactivation of tumor suppressor genes (TSGs). An unmet need in the field is the translation of the genomic landscape into effective TSG-specific therapies. Methods: We correlated genomes against transcriptomes of patients' MPM tumors, by weighted gene co-expression network analysis (WGCNA). The identified aberrant biochemical networks and potential drug targets induced by tumor suppressor loss were validated by integrative data analysis and functional interrogation. Results: CDKN2A/2B loss activates G2/M checkpoint and PI3K/AKT, prioritizing a co-targeting strategy for CDKN2A/2B-null MPM. CDKN2A deficiency significantly co-occurs with deletions of anti-viral type I interferon (IFN-I) genes and BAP1 mutations, that enriches the IFN-I signature, stratifying a unique subset, with deficient IFN-I, but proficient BAP1 for oncolytic viral immunotherapies. Aberrant p53 attenuates differentiation and SETD2 loss acquires the dependency on EGFRs, highlighting the potential of differentiation therapy and pan-EGFR inhibitors for these subpopulations, respectively. LATS2 deficiency is linked with dysregulated immunoregulation, suggesting a rationale for immune checkpoint blockade. Finally, multiple lines of evidence support Dasatinib as a promising therapeutic for LATS2-mutant MPM. Conclusions: Systematic identification of abnormal cellular processes and potential drug vulnerabilities specified by TSG alterations provide a framework for precision oncology in MPM.

SUBMITTER: Yang H

PROVIDER: S-EPMC7465812 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma.

Yang Haitang H Xu Duo D Yang Zhang Z Yao Feng F Zhao Heng H Schmid Ralph A RA Peng Ren-Wang RW

Cancers 20200817 8

<i>Background</i>: Malignant pleural mesothelioma (MPM) is driven by the inactivation of tumor suppressor genes (TSGs). An unmet need in the field is the translation of the genomic landscape into effective TSG-specific therapies. <i>Methods</i>: We correlated genomes against transcriptomes of patients' MPM tumors, by weighted gene co-expression network analysis (WGCNA). The identified aberrant biochemical networks and potential drug targets induced by tumor suppressor loss were validated by inte ...[more]

PMID: 32824422

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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.

Dataset Information

Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma.

Publications

Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma.

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