{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T12:21:26Z","timestamp":1769948486282,"version":"3.49.0"},"reference-count":57,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acellular bronchoalveolar lavage (BAL) proteomics can partially separate lung cancer from non-lung cancer patients based on principal component analysis and multivariate analysis. Furthermore, the variance in the proteomics data sets is correlated mainly with lung cancer status and, to a lesser extent, smoking status and gender. Despite these advances BAL small and large extracellular vehicles (EVs) proteomes reveal aberrant protein expression in paracrine signaling mechanisms in cancer initiation and progression. We consequently present a case-control study of 24 bronchoalveolar lavage extracellular vesicle samples which were analyzed by state-of-the-art liquid chromatography-mass spectrometry (LC-MS). We obtained evidence that BAL EVs proteome complexity correlated with lung cancer stage 4 and mortality within two years\u00b4 follow-up (p value = 0.006). The potential therapeutic target DNMT3B complex is significantly up-regulated in tumor tissue and BAL EVs. The computational analysis of the immune and fibroblast cell markers in EVs suggests that patients who deceased within the follow-up period display higher marker expression indicative of innate immune and fibroblast cells (four out of five cases). This study provides insights into the proteome content of BAL EVs and their correlation to clinical outcomes.<\/jats:p>","DOI":"10.3390\/cancers12113450","type":"journal-article","created":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T09:46:18Z","timestamp":1605865578000},"page":"3450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer?"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0657-1907","authenticated-orcid":false,"given":"Ana Sofia","family":"Carvalho","sequence":"first","affiliation":[{"name":"Computational and Experimental Biology Group, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Campo dos Martires da Patria, 130, 1169-056 Lisboa, Portugal"}]},{"given":"Maria Carolina Strano","family":"Moraes","sequence":"additional","affiliation":[{"name":"Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, Av. Brasilia, Doca de Pedroucos, 1400-038 Lisbon, Portugal"}]},{"given":"Chan","family":"Hyun Na","sequence":"additional","affiliation":[{"name":"Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5460-2117","authenticated-orcid":false,"given":"Ivo","family":"Fierro-Monti","sequence":"additional","affiliation":[{"name":"Computational and Experimental Biology Group, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Campo dos Martires da Patria, 130, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7763-873X","authenticated-orcid":false,"given":"Andreia","family":"Henriques","sequence":"additional","affiliation":[{"name":"Computational and Experimental Biology Group, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Campo dos Martires da Patria, 130, 1169-056 Lisboa, Portugal"}]},{"given":"Sara","family":"Zahedi","sequence":"additional","affiliation":[{"name":"Computational and Experimental Biology Group, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Campo dos Martires da Patria, 130, 1169-056 Lisboa, Portugal"}]},{"given":"Cristian","family":"Bodo","sequence":"additional","affiliation":[{"name":"Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, Av. Brasilia, Doca de Pedroucos, 1400-038 Lisbon, Portugal"}]},{"given":"Erin M","family":"Tranfield","sequence":"additional","affiliation":[{"name":"Electron Microscopy Facility, Instituto Gulbenkian de Ci\u00eancia\u2014Rua da Quinta Grande, 6, 2780-156 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6067-8794","authenticated-orcid":false,"given":"Ana Laura","family":"Sousa","sequence":"additional","affiliation":[{"name":"Electron Microscopy Facility, Instituto Gulbenkian de Ci\u00eancia\u2014Rua da Quinta Grande, 6, 2780-156 Oeiras, Portugal"}]},{"given":"Ana","family":"Farinho","sequence":"additional","affiliation":[{"name":"iNOVA4Health\u2014Advancing Precision Medicine, CEDOC\u2014Chronic Diseases Research Centre, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos Martires da Patria, 130, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5929-6078","authenticated-orcid":false,"given":"Lu\u00eds Vaz","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Unidade Local de Sa\u00fade da Guarda (USLGuarda), 6300-659 Guarda, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2301-2752","authenticated-orcid":false,"given":"Paula","family":"Pinto","sequence":"additional","affiliation":[{"name":"Unidade de T\u00e9cnicas Invasivas Pneumol\u00f3gicas, Pneumologia II, Hospital Pulido Valente, Centro Hospitalar Lisboa Norte, 1649-028 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0915-4105","authenticated-orcid":false,"given":"Cristina","family":"B\u00e1rbara","sequence":"additional","affiliation":[{"name":"Instituto de Sa\u00fade Ambiental (ISAMB), Faculdade de Medicina, Universidade de Lisboa, Centro Hospitalar Universit\u00e1rio Lisboa Norte, 1649-028 Lisbon, Portugal"}]},{"given":"Leonor","family":"Mota","sequence":"additional","affiliation":[{"name":"Unidade de T\u00e9cnicas Invasivas Pneumol\u00f3gicas, Pneumologia II, Hospital Pulido Valente, Centro Hospitalar Lisboa Norte, 1649-028 Lisbon, Portugal"}]},{"given":"Tiago Tavares de","family":"Abreu","sequence":"additional","affiliation":[{"name":"Unidade de T\u00e9cnicas Invasivas Pneumol\u00f3gicas, Pneumologia II, Hospital Pulido Valente, Centro Hospitalar Lisboa Norte, 1649-028 Lisbon, Portugal"}]},{"given":"J\u00falio","family":"Semedo","sequence":"additional","affiliation":[{"name":"Unidade de T\u00e9cnicas Invasivas Pneumol\u00f3gicas, Pneumologia II, Hospital Pulido Valente, Centro Hospitalar Lisboa Norte, 1649-028 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7035-7422","authenticated-orcid":false,"given":"Susana","family":"Seixas","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (I3S), Universidade do Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8975-5108","authenticated-orcid":false,"given":"Prashant","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics, Discoverer building, ITPL, Bangalore 560066, India"},{"name":"Manipal Academy of Higher Education (MAHE), Manipal 576104, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5932-6211","authenticated-orcid":false,"given":"Bruno","family":"Costa-Silva","sequence":"additional","affiliation":[{"name":"Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, Av. Brasilia, Doca de Pedroucos, 1400-038 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9943-6127","authenticated-orcid":false,"given":"Akhilesh","family":"Pandey","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics, Discoverer building, ITPL, Bangalore 560066, India"},{"name":"Manipal Academy of Higher Education (MAHE), Manipal 576104, India"},{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6353-2616","authenticated-orcid":false,"given":"Rune","family":"Matthiesen","sequence":"additional","affiliation":[{"name":"Computational and Experimental Biology Group, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Campo dos Martires da Patria, 130, 1169-056 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1177\/1403494817715400","article-title":"The global cancer burden and human development: A review","volume":"46","author":"Fidler","year":"2018","journal-title":"Scand. J. Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.5334\/aogh.2419","article-title":"Global Epidemiology of Lung Cancer","volume":"85","author":"Barta","year":"2019","journal-title":"Ann. Glob. Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5792","DOI":"10.1158\/1078-0432.CCR-17-3620","article-title":"The Integration of Radiotherapy with Immunotherapy for the Treatment of Non-Small Cell Lung Cancer","volume":"24","author":"Ko","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1900077","DOI":"10.1002\/prca.201900077","article-title":"MS-Based Biomarker Discovery in Bronchoalveolar Lavage Fluid for Lung Cancer","volume":"14","author":"Matthiesen","year":"2020","journal-title":"Proteom. Clin. Appl."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jconrel.2018.12.008","article-title":"Identification of miRNA-rich vesicles in bronchoalveolar lavage fluid: Insights into the function and heterogeneity of extracellular vesicles","volume":"294","author":"Lee","year":"2019","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.4049\/jimmunol.1900039","article-title":"Epithelial Expression of an Interstitial Lung Disease-Associated Mutation in Surfactant Protein-C Modulates Recruitment and Activation of Key Myeloid Cell Populations in Mice","volume":"202","author":"Venosa","year":"2019","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.7150\/jca.21368","article-title":"DNA Methylation Analysis of the SHOX2 and RASSF1A Panel in Bronchoalveolar Lavage Fluid for Lung Cancer Diagnosis","volume":"8","author":"Zhang","year":"2017","journal-title":"J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"180060","DOI":"10.1038\/sdata.2018.60","article-title":"A prototypic small molecule database for bronchoalveolar lavage-based metabolomics","volume":"5","author":"Walmsley","year":"2018","journal-title":"Sci. Data"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12838","DOI":"10.1038\/s41598-019-49195-w","article-title":"Profiling of lung microbiota discloses differences in adenocarcinoma and squamous cell carcinoma","volume":"9","author":"Gomes","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.lungcan.2011.01.015","article-title":"Bronchoalveolar lavage fluid of lung cancer patients: Mapping the uncharted waters using proteomics technology","volume":"72","author":"Oumeraci","year":"2011","journal-title":"Lung Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.jprot.2013.04.037","article-title":"Identification of proteomic signatures associated with lung cancer and COPD","volume":"89","author":"Pastor","year":"2013","journal-title":"J. Proteom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"42190","DOI":"10.1038\/srep42190","article-title":"Bronchoalveolar Lavage Proteomics in Patients with Suspected Lung Cancer","volume":"7","author":"Carvalho","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","first-page":"39","article-title":"Quantitative proteomics of bronchoalveolar lavage fluid in lung adenocarcinoma","volume":"12","author":"Almatroodi","year":"2015","journal-title":"Cancer Genom. Proteom."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jprot.2016.02.010","article-title":"Discovery of potential protein biomarkers of lung adenocarcinoma in bronchoalveolar lavage fluid by SWATH MS data-independent acquisition and targeted data extraction","volume":"138","author":"Ortea","year":"2016","journal-title":"J. Proteom."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e1900028","DOI":"10.1002\/prca.201900028","article-title":"In-Depth Proteomic Analysis of Human Bronchoalveolar Lavage Fluid toward the Biomarker Discovery for Lung Cancers","volume":"13","author":"Sim","year":"2019","journal-title":"Proteom. Clin. Appl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"398","DOI":"10.2741\/4811","article-title":"Extra-cellular vesicles carry proteome of cancer hallmarks","volume":"25","author":"Carvalho","year":"2020","journal-title":"Front. Biosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5469","DOI":"10.1038\/ncomms6469","article-title":"Integrated omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact","volume":"5","author":"Li","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"86999","DOI":"10.18632\/oncotarget.13569","article-title":"Proteomic profiling of NCI-60 extracellular vesicles uncovers common protein cargo and cancer type-specific biomarkers","volume":"7","author":"Hurwitz","year":"2016","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.cell.2020.07.009","article-title":"Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers","volume":"182","author":"Hoshino","year":"2020","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"18826","DOI":"10.1038\/srep18826","article-title":"New insights into functional regulation in MS-based drug profiling","volume":"6","author":"Carvalho","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3109\/01902148.2013.781720","article-title":"Isolation of fibroblasts and epithelial cells in bronchoalveolar lavage (BAL)","volume":"39","author":"Pollock","year":"2013","journal-title":"Exp. Lung Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Webber, J., and Clayton, A. (2013). How pure are your vesicles?. J. Extracell. Vesicles, 2.","DOI":"10.3402\/jev.v2i0.19861"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1038\/s41596-019-0133-y","article-title":"Mass spectrometry-based identification of MHC-bound peptides for immunopeptidomics","volume":"14","author":"Purcell","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18769","DOI":"10.1073\/pnas.1008501107","article-title":"Soluble plasma HLA peptidome as a potential source for cancer biomarkers","volume":"107","author":"Barnea","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"36338","DOI":"10.1038\/srep36338","article-title":"Detailed Analysis of Protein Topology of Extracellular Vesicles-Evidence of Unconventional Membrane Protein Orientation","volume":"6","author":"Cvjetkovic","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1038\/sj.onc.1210422","article-title":"Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer","volume":"26","author":"Roberts","year":"2007","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/onc.2016.195","article-title":"The ERK-ZEB1 pathway mediates epithelial-mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids","volume":"36","author":"Chiu","year":"2017","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41389-020-00262-2","article-title":"Squalene synthase promotes the invasion of lung cancer cells via the osteopontin\/ERK pathway","volume":"9","author":"Yang","year":"2020","journal-title":"Oncogenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1038\/s41467-019-10367-x","article-title":"SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers","volume":"10","author":"Jones","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12943-019-0965-7","article-title":"Extracellular vesicles-mediated intercellular communication: Roles in the tumor microenvironment and anti-cancer drug resistance","volume":"18","author":"Maacha","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"15336","DOI":"10.1073\/pnas.1102855108","article-title":"Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3","volume":"108","author":"Aung","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5553","DOI":"10.1038\/sj.onc.1210351","article-title":"Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins","volume":"26","author":"Ostler","year":"2007","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41392-019-0095-0","article-title":"Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials","volume":"4","author":"Cheng","year":"2019","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s10549-011-1409-2","article-title":"Enhancement of chemotherapeutic efficacy in hypermethylator breast cancer cells through targeted and pharmacologic inhibition of DNMT3b","volume":"131","author":"Sandhu","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.omto.2020.04.007","article-title":"Radiation-Induced DNMT3B Promotes Radioresistance in Nasopharyngeal Carcinoma through Methylation of p53 and p21","volume":"17","author":"Wu","year":"2020","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17113","DOI":"10.1074\/jbc.M117.810309","article-title":"Evidence for a direct cross-talk between malic enzyme and the pentose phosphate pathway via structural interactions","volume":"292","author":"Yao","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc2748","article-title":"Integrins in cancer: Biological implications and therapeutic opportunities","volume":"10","author":"Desgrosellier","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/bjc.2016.312","article-title":"The complexity of integrins in cancer and new scopes for therapeutic targeting","volume":"115","author":"Hamidi","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_42","first-page":"43","article-title":"Immune cells in bronchoalveolar lavage in peripheral lung cancer\u2014Analysis of 140 cases","volume":"70","author":"Guzman","year":"2003","journal-title":"Respir. Int. Rev. Thorac. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1158\/2326-6066.CIR-17-0075","article-title":"Antigen-Presenting Intratumoral B Cells Affect CD4(+) TIL Phenotypes in Non-Small Cell Lung Cancer Patients","volume":"5","author":"Bruno","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature14424","article-title":"Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity","volume":"521","author":"Carmi","year":"2015","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1148\/radiol.2372041887","article-title":"Guidelines for management of small pulmonary nodules detected on CT scans: A statement from the Fleischner Society","volume":"237","author":"MacMahon","year":"2005","journal-title":"Radiology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Wisniewski","year":"2009","journal-title":"Nat. Methods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1074\/mcp.M113.034363","article-title":"Global mass spectrometry and transcriptomics array based drug profiling provides novel insight into glucosamine induced endoplasmic reticulum stress","volume":"13","author":"Carvalho","year":"2014","journal-title":"Mol. Cell. Proteom. MCP"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/nbt.1511","article-title":"MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification","volume":"26","author":"Cox","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4176","DOI":"10.1016\/j.jprot.2012.05.010","article-title":"SIR: Deterministic protein inference from peptides assigned to MS data","volume":"75","author":"Matthiesen","year":"2012","journal-title":"J. Proteom."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1093\/bioinformatics\/btn178","article-title":"Annotation-Modules: A tool for finding significant combinations of multisource annotations for gene lists","volume":"24","author":"Hackenberg","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Gene Ontology Consortium (2019). The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res., 47, D330\u2013D338.","DOI":"10.1093\/nar\/gky1055"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1039\/C1MB05340J","article-title":"Human Protein Reference Database and Human Proteinpedia as resources for phosphoproteome analysis","volume":"8","author":"Goel","year":"2012","journal-title":"Mol. Biosyst."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"D646","DOI":"10.1093\/nar\/gkm936","article-title":"CORUM: The comprehensive resource of mammalian protein complexes","volume":"36","author":"Ruepp","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_57","first-page":"D442","article-title":"The PRIDE database and related tools and resources in 2019: Improving support for quantification data","volume":"47","author":"Csordas","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3450\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:34:44Z","timestamp":1760178884000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,20]]},"references-count":57,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cancers12113450"],"URL":"https:\/\/doi.org\/10.3390\/cancers12113450","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,20]]}}}