{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T06:42:47Z","timestamp":1762324967264,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-016390:CANCEL STEM","SFRH\/BD\/105694\/2015"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016390:CANCEL STEM","SFRH\/BD\/105694\/2015"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Research Foundation","award":["SCHU 2670\/1"],"award-info":[{"award-number":["SCHU 2670\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Altered metabolic processes contribute to carcinogenesis by modulating proliferation, survival and differentiation. Tumours are composed of different cell populations, with cancer stem-like cells being one of the most prominent examples. This specific pool of cells is thought to be responsible for cancer growth and recurrence and plays a particularly relevant role in glioblastoma (GBM), the most lethal form of primary brain tumours. Here, we have analysed the transcriptome and metabolome of an established GBM cell line (U87) and a patient-derived GBM stem-like cell line (NCH644) exposed to neurosphere or monolayer culture conditions. By integrating transcriptome and metabolome data, we identified key metabolic pathways and gene signatures that are associated with stem-like and differentiated states in GBM cells, and demonstrated that neurospheres and monolayer cells differ substantially in their metabolism and gene regulation. Furthermore, arginine biosynthesis was identified as the most significantly regulated pathway in neurospheres, although individual nodes of this pathway were distinctly regulated in the two cellular systems. Neurosphere conditions, as opposed to monolayer conditions, cause a transcriptomic and metabolic rewiring that may be crucial for the regulation of stem-like features, where arginine biosynthesis may be a key metabolic pathway. Additionally, TCGA data from GBM patients showed significant regulation of specific components of the arginine biosynthesis pathway, providing further evidence for the importance of this metabolic pathway in GBM.<\/jats:p>","DOI":"10.3390\/cancers13061327","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T12:04:00Z","timestamp":1615896240000},"page":"1327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Integrated Metabolomics and Transcriptomics Analysis of Monolayer and Neurospheres from Established Glioblastoma Cell Lines"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9469-5680","authenticated-orcid":false,"given":"Joana","family":"Peixoto","sequence":"first","affiliation":[{"name":"Cancer Signalling and Metabolism Group, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Signalling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-465 Porto, Portugal"},{"name":"Faculty of Medical, University of Porto, 4200-319 Porto, Portugal"},{"name":"Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 W\u00fcrzburg, Germany"}]},{"given":"Sudha","family":"Janaki-Raman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 W\u00fcrzburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-2289","authenticated-orcid":false,"given":"Lisa","family":"Schlicker","sequence":"additional","affiliation":[{"name":"Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0485-7303","authenticated-orcid":false,"given":"Werner","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 W\u00fcrzburg, Germany"}]},{"given":"Susanne","family":"Walz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 W\u00fcrzburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7728-0715","authenticated-orcid":false,"given":"Alina M.","family":"Winkelkotte","sequence":"additional","affiliation":[{"name":"Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany"},{"name":"Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1915-745X","authenticated-orcid":false,"given":"Christel","family":"Herold-Mende","sequence":"additional","affiliation":[{"name":"Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, 69117 Heidelberg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9607-6998","authenticated-orcid":false,"given":"Paula","family":"Soares","sequence":"additional","affiliation":[{"name":"Cancer Signalling and Metabolism Group, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Signalling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-465 Porto, Portugal"},{"name":"Faculty of Medical, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8199-6422","authenticated-orcid":false,"given":"Almut","family":"Schulze","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 W\u00fcrzburg, Germany"},{"name":"Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7780-0901","authenticated-orcid":false,"given":"Jorge","family":"Lima","sequence":"additional","affiliation":[{"name":"Cancer Signalling and Metabolism Group, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Signalling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-465 Porto, Portugal"},{"name":"Faculty of Medical, University of Porto, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nature03128","article-title":"Identification of human brain tumour initiating cells","volume":"432","author":"Singh","year":"2004","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.ccr.2006.03.030","article-title":"Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines","volume":"9","author":"Lee","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/nature05236","article-title":"Glioma stem cells promote radioresistance by preferential activation of the DNA damage 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