{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T13:43:08Z","timestamp":1786542188543,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive metabolic reprogramming, yet how major metabolic pathways are organized at single-cell resolution, and how this relates to the tumor microenvironment and therapeutic vulnerabilities, remains incompletely understood. We analyzed 32,227 cells from the GSE155698 discovery cohort and 32,627 cells from an independent healthy-pancreas reference (GSE229413; n = 5 donors) and introduce the Metabolic Rheostat Index (MRI), the standard deviation across per-cell glycolysis, OXPHOS, and hypoxia pathway scores. A pseudobulk analysis, hallmark gene-set validation, unified-threshold classification, a GDSC2 drug-sensitivity analysis with robust regression, EPIC tumor-purity-adjusted deconvolution, and a survival analysis of 183 TCGA-PAAD samples were performed. The pseudobulk analysis revealed a monotonic MRI gradient from healthy pancreata (mean = 0.259) to adjacent-normal tissue (0.322) to PDAC tumor tissue (0.352; p = 0.0039, Cohen\u2019s d = 1.437), indicating progressive metabolic polarization during malignant transformation driven predominantly by cancer-associated fibroblasts rather than malignant epithelial cells. The glycolysis\u2013hypoxia correlation was stronger in tumor cells (r = 0.121 vs. 0.019), and ERK\/MAPK inhibitors showed the greatest drug sensitivity (r = 0.597, p = 0.0008). The Warburg Index correlated with fibroblast infiltration (partial r = 0.312, p = 1.76 \u00d7 10\u22125) but was not an independent prognostic marker (HR = 0.78, p = 0.321). These findings indicate that PDAC tissue undergoes progressive, stroma-driven metabolic polarization associated with an immunosuppressive microenvironment, providing a multi-dimensional single-cell framework for future metabolic-targeted therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cimb48080820","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T12:53:48Z","timestamp":1786539228000},"page":"820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Metabolic Rheostat Index Uncovers Pathway-Level Coordination, Immunosuppressive Microenvironment Remodeling, and Therapeutic Co-Vulnerabilities in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3978-9427","authenticated-orcid":false,"given":"Funda","family":"Demirtas Korkmaz","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Giresun University, 28200 Giresun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-8898","authenticated-orcid":false,"given":"Yasemin","family":"Sevim","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Giresun University, 28200 Giresun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6420-6292","authenticated-orcid":false,"given":"Zekeriya","family":"Duzgun","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Giresun University, 28200 Giresun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3248-4279","authenticated-orcid":false,"given":"Asuman","family":"Deveci Ozkan","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Sakarya University, 54290 Sakarya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41575-023-00840-w","article-title":"Therapeutic Developments in Pancreatic Cancer","volume":"21","author":"Hu","year":"2024","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/nrc949","article-title":"Pancreatic Cancer Biology and Genetics","volume":"2","author":"Bardeesy","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/s41571-025-01077-z","article-title":"The Tumour Microenvironment in Pancreatic Cancer\u2014New Clinical Challenges, But More Opportunities","volume":"22","author":"Kung","year":"2025","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ccell.2016.12.006","article-title":"Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer","volume":"31","author":"Halbrook","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature12040","article-title":"Glutamine Supports Pancreatic Cancer Growth through a KRAS-Regulated Metabolic Pathway","volume":"496","author":"Son","year":"2013","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.4161\/cc.25307","article-title":"Pancreatic Cancers Rely on a Novel Glutamine Metabolism Pathway to Maintain Redox Balance","volume":"12","author":"Lyssiotis","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1053\/j.seminoncol.2017.10.004","article-title":"Metabolic Coupling and the Reverse Warburg Effect in Cancer: Implications for Novel Biomarker and Anticancer Agent Development","volume":"44","author":"Wilde","year":"2017","journal-title":"Semin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.cmet.2022.01.007","article-title":"The Hallmarks of Cancer Metabolism: Still Emerging","volume":"34","author":"Pavlova","year":"2022","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114633","DOI":"10.1016\/j.celrep.2024.114633","article-title":"A CLIC1 Network Coordinates Matrix Stiffness and the Warburg Effect to Promote Tumor Growth in Pancreatic Cancer","volume":"43","author":"Zheng","year":"2024","journal-title":"Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41586-019-1832-9","article-title":"KRAS4A Directly Regulates Hexokinase 1","volume":"576","author":"Amendola","year":"2019","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1136\/gutjnl-2018-317163","article-title":"Localisation of PGK1 Determines Metabolic Phenotype to Balance Metastasis and Proliferation in Patients with SMAD4-Negative Pancreatic Cancer","volume":"69","author":"Liang","year":"2020","journal-title":"Gut"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6119","DOI":"10.1016\/j.cell.2021.11.017","article-title":"Microenvironment Drives Cell State, Plasticity, and Drug Response in Pancreatic Cancer","volume":"184","author":"Raghavan","year":"2021","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.trecan.2019.11.010","article-title":"Tumor Functional Heterogeneity Unraveled by scRNA-Seq Technologies","volume":"6","author":"Quevedo","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105389","DOI":"10.1016\/j.ebiom.2024.105389","article-title":"Single Cell Atlas Reveals Multilayered Metabolic Heterogeneity across Tumour Types","volume":"109","author":"Zhou","year":"2024","journal-title":"eBioMedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1038\/s41588-022-01134-8","article-title":"Single-Nucleus and Spatial Transcriptome Profiling of Pancreatic Cancer Identifies Multicellular Dynamics Associated with Neoadjuvant Treatment","volume":"54","author":"Hwang","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e163022","DOI":"10.1172\/jci.insight.163022","article-title":"Cancer-Associated Fibroblasts Reuse Cancer-Derived Lactate to Maintain a Fibrotic and Immunosuppressive Microenvironment in Pancreatic Cancer","volume":"8","author":"Kitamura","year":"2023","journal-title":"JCI Insight"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s43018-020-00121-4","article-title":"Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer","volume":"1","author":"Steele","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/s41467-023-36296-4","article-title":"Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and Its Tumor Microenvironment","volume":"14","author":"Werba","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1158\/2159-8290.CD-23-0013","article-title":"Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions","volume":"13","author":"Carpenter","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nature11005","article-title":"Systematic Identification of Genomic Markers of Drug Sensitivity in Cancer Cells","volume":"483","author":"Garnett","year":"2012","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D955","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of Drug Sensitivity in Cancer (GDSC): A Resource for Therapeutic Biomarker Discovery in Cancer Cells","volume":"41","author":"Yang","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING Database in 2021: Customizable Protein-Protein Networks, and Functional Characterization of User-Uploaded Gene\/Measurement Sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_25","unstructured":"Cs\u00e1rdi, G., and Nepusz, T. (2006). The igraph Software Package for Complex Network Research. InterJournal, 1695."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e26476","DOI":"10.7554\/eLife.26476","article-title":"Simultaneous Enumeration of Cancer and Immune Cell Types from Bulk Tumor Gene Expression Data","volume":"6","author":"Racle","year":"2017","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4686","DOI":"10.1038\/s41388-022-02448-x","article-title":"The Roles of Intratumour Heterogeneity in the Biology and Treatment of Pancreatic Ductal Adenocarcinoma","volume":"41","author":"Evan","year":"2022","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-Inducible Factors in Physiology and Medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41392-025-02546-8","article-title":"Glycolytic Heterogeneity Drives Metabolic-Targeted Therapy in Pancreatic Ductal Adenocarcinoma","volume":"11","author":"Chianese","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/ng.3398","article-title":"Virtual Microdissection Identifies Distinct Tumor- and Stroma-Specific Subtypes of Pancreatic Ductal Adenocarcinoma","volume":"47","author":"Moffitt","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1158\/1078-0432.CCR-24-2183","article-title":"Human Pancreatic Cancer Single-Cell Atlas Reveals Association of CXCL10+ Fibroblasts and Basal Subtype Tumor Cells","volume":"31","author":"Loveless","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s43018-023-00526-x","article-title":"Single-Cell Profiling to Explore Pancreatic Cancer Heterogeneity, Plasticity and Response to Therapy","volume":"4","author":"Rad","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ccell.2020.06.012","article-title":"Emergence of a High-Plasticity Cell State During Lung Cancer Evolution","volume":"38","author":"Marjanovic","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1158\/2159-8290.CD-20-0844","article-title":"Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy","volume":"10","author":"Fendt","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.immuni.2022.01.006","article-title":"Tryptophan-Derived Microbial Metabolites Activate the Aryl Hydrocarbon Receptor in Tumor-Associated Macrophages to Suppress Anti-Tumor Immunity","volume":"55","author":"Hezaveh","year":"2022","journal-title":"Immunity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"eaaw5473","DOI":"10.1126\/science.aaw5473","article-title":"Metabolic Reprogramming and Cancer Progression","volume":"368","author":"Faubert","year":"2020","journal-title":"Science"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/820\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T13:25:21Z","timestamp":1786541121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cimb48080820"],"URL":"https:\/\/doi.org\/10.3390\/cimb48080820","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]}}}