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Multicellular gene network analysis identifies a macrophage-related gene signature predictive of therapeutic response and prognosis of gliomas
Sun X.1,2; Liu X.3; Xia M.1; Shao Y.4; Zhang X.D.5
2019
Source PublicationJournal of Translational Medicine
ISSN1479-5876
Volume17Issue:1
Abstract

Background: The tumor-associated microenvironment plays important roles in tumor progression and drug resistance. However, systematic investigations of macrophage-tumor cell interactions to identify novel macrophage-related gene signatures in gliomas for predicting patient prognoses and responses to targeted therapies are lacking. Methods: We developed a multicellular gene network approach to investigating the prognostic role of macrophage-tumor cell interactions in tumor progression and drug resistance in gliomas. Multicellular gene networks connecting macrophages and tumor cells were constructed from re-grouped drug-sensitive and drug-resistant samples of RNA-seq data in mice gliomas treated with BLZ945 (a CSF1R inhibitor). Subsequently, a differential network-based COX regression model was built to identify the risk signature using a cohort of 310 glioma samples from the Chinese Glioma Genome Atlas database. A large independent validation set of 690 glioma samples from The Cancer Genome Atlas database was used to test the prognostic significance and accuracy of the gene signature in predicting prognosis and targeted therapeutic response of glioma patients. Results: A macrophage-related gene signature was developed consisting of twelve genes (ANPEP, DPP4, PRRG1, GPNMB, TMEM26, PXDN, CDH6, SCN3A, SEMA6B, CCDC37, FANCA, NETO2), which was tested in the independent validation set to examine its prognostic significance and accuracy. The generation of 1000 random gene signatures by a bootstrapping scheme justified the non-random nature of the macrophage-related gene signature. Moreover, the discovered gene signature was verified to be predictive of the sensitivity or resistance of glioma patients to molecularly targeted therapeutics and outperformed other existing gene signatures. Additionally, the macrophage-related gene signature was an independent and the strongest prognostic factor when adjusted for clinicopathologic risk factors and other existing gene signatures. Conclusion: The multicellular gene network approach developed herein indicates profound roles of the macrophage-mediated tumor microenvironment in the progression and drug resistance of gliomas. The identified macrophage-related gene signature has good prognostic value for predicting resistance to targeted therapeutics and survival of glioma patients, implying that combining current targeted therapies with new macrophage-targeted therapy may be beneficial for the long-term treatment outcomes of glioma patients. 

KeywordBiomarker Drug Resistance Glioma Macrophages Multicellular Gene Network Prognostic Signature
DOI10.1186/s12967-019-1908-1
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaResearch & Experimental Medicine
WOS SubjectMedicine, Research & Experimental
WOS IDWOS:000468457000002
The Source to ArticleScopus
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Cited Times [WOS]:13   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorSun X.; Shao Y.; Zhang X.D.
Affiliation1.Department of Medical Informatics, Zhong-shan School of Medicine, Sun Yat-Sen University, Guangzhou, 510089, China;
2.School of Mathematics, Sun Yat-Sen University, Guangzhou, 510089, China;
3.School of Mathematics and Statistics, Shandong University at Weihai, Weihai, China;
4.NYU School of Medicine, NYU Langone Health, New York University, New York, NY 10016, United States;
5.Faculty of Health Sciences, University of Macau, Taipa, Macau
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Sun X.,Liu X.,Xia M.,et al. Multicellular gene network analysis identifies a macrophage-related gene signature predictive of therapeutic response and prognosis of gliomas[J]. Journal of Translational Medicine,2019,17(1).
APA Sun X.,Liu X.,Xia M.,Shao Y.,&Zhang X.D..(2019).Multicellular gene network analysis identifies a macrophage-related gene signature predictive of therapeutic response and prognosis of gliomas.Journal of Translational Medicine,17(1).
MLA Sun X.,et al."Multicellular gene network analysis identifies a macrophage-related gene signature predictive of therapeutic response and prognosis of gliomas".Journal of Translational Medicine 17.1(2019).
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