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However, the impact of systemic metabolism and diet on tumour evolution is less understood. This study delves into the role of glucagon, as a component of the pancreatic microenvironment, in regulating features of pancreatic neuroendocrine tumour (pNET) cells and the metabolic remodelling occurring in the presence and absence of glucose. pNET cell lines (BON-1 and QGP-1) and the non-malignant pancreatic \u03b1-TC1 cell line were used as models. Results showed that pNET cells responded differently to glucose deprivation than \u03b1-TC1 cells. Specifically, pNET cells upregulated the GCGR in the absence of glucose, while \u03b1-TC1 cells did so in high-glucose conditions, allowing the glucagon-related pERK1\/2 activation under these conditions in pNET cells. Glucagon enhanced cancerous features in pNET BON-1 cells under glucose-deprived and hyperglucagonemia-compatible concentrations. In the \u03b1-TC1 cell line, glucagon modulated cell features under high-glucose and physiological glucagon levels. NMR exometabolome analysis revealed differences in metabolic processes based on glucose availability and glucagon stimulation across cell lines, highlighting amino acid metabolism, glycolysis, and gluconeogenesis. The expression of metabolic genes was consistent with these findings. Interestingly, QGP-1 and \u03b1-TC1 cells produced glucose in no-glucose conditions, and glucagon upregulated glucose production in \u03b1-TC1 cells. This suggests that gluconeogenesis may be beneficial for some pNET subsets, pointing out novel metabolism-based strategies to manage pNETs, as well as a step forward in endocrinology and systemic metabolism. The association between GCGR expression and malignancy and a negative correlation between glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) expression was observed, indicating a biological role of glucagon in pNETs that deserves to be explored.<\/jats:p>","DOI":"10.3390\/molecules30132736","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T08:23:22Z","timestamp":1750839802000},"page":"2736","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Glucagon and Glucose Availability Influence Metabolic Heterogeneity and Malignancy in Pancreatic Neuroendocrine Tumour (pNET) Cells: Novel Routes for Therapeutic Targeting"],"prefix":"10.3390","volume":"30","author":[{"given":"B\u00e1rbara","family":"Ferreira","sequence":"first","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Portuguese Institute of Oncology of Lisbon Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0568-905X","authenticated-orcid":false,"given":"Isabel","family":"Lemos","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Portuguese Institute of Oncology of Lisbon Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8808-5082","authenticated-orcid":false,"given":"Cindy","family":"Mendes","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Portuguese Institute of Oncology of Lisbon Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9132-8586","authenticated-orcid":false,"given":"Beatriz","family":"Chumbinho","sequence":"additional","affiliation":[{"name":"Universitary Center and Hospital of Central Lisbon, Hospital Curry Cabral, Rua da Benefic\u00eancia, 1069-166 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-6493","authenticated-orcid":false,"given":"Fernanda","family":"Silva","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"}]},{"given":"Daniela","family":"Pereira","sequence":"additional","affiliation":[{"name":"Portuguese Institute of Oncology of Lisbon Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"given":"Emanuel","family":"Vigia","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Universitary Center and Hospital of Central Lisbon, Hospital Curry Cabral, Rua da Benefic\u00eancia, 1069-166 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5683-3552","authenticated-orcid":false,"given":"Lu\u00eds G.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Institute of Chemical and Biological Tecnology Ant\u00f3nio Xavier (ITQB NOVA), Avenida da Rep\u00fablica (EAN), 2780-157 Oeiras, Portugal"}]},{"given":"Ant\u00f3nio","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Universitary Center and Hospital of Central Lisbon, Hospital Curry Cabral, Rua da Benefic\u00eancia, 1069-166 Lisboa, Portugal"}]},{"given":"Daniela","family":"Cavaco","sequence":"additional","affiliation":[{"name":"Portuguese Institute of Oncology of Lisbon Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1548-5907","authenticated-orcid":false,"given":"Jacinta","family":"Serpa","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Portuguese Institute of Oncology of Lisbon Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nrc.2016.100","article-title":"The Current State of Cancer Metabolism","volume":"16","author":"Cairns","year":"2016","journal-title":"Nat. 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