{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:12:35Z","timestamp":1785413555590,"version":"3.56.0"},"reference-count":77,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016047","name":"Science Fund of the Republic of Serbia","doi-asserted-by":"publisher","award":["6056979"],"award-info":[{"award-number":["6056979"]}],"id":[{"id":"10.13039\/501100016047","id-type":"DOI","asserted-by":"publisher"}]},{"award":["6056979"],"award-info":[{"award-number":["6056979"]}],"id":[{"id":"https:\/\/ror.org\/02r531a15","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministry of Education, Science, and Technological Development of the Republic of Serbia Agreements","award":["451-03-66\/2024-03\/200043"],"award-info":[{"award-number":["451-03-66\/2024-03\/200043"]}]},{"name":"Ministry of Education, Science, and Technological Development of the Republic of Serbia Agreements","award":["451-03-66\/2024-03\/200042"],"award-info":[{"award-number":["451-03-66\/2024-03\/200042"]}]},{"DOI":"10.13039\/501100000780","name":"European Union\u2019s Horizon 2020 Research and Innovation Programme under the Marie Sk\u0142odowska-Curie","doi-asserted-by":"publisher","award":["891135"],"award-info":[{"award-number":["891135"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types with a dismal prognosis, where early metastatic dissemination and rich desmoplastic stroma limit the therapeutic efficacy. Nischarin (NISCH)\/Imidazoline-1 receptor (IR-1) is a potential tumor suppressor that is involved in the regulation of cell migration, invasion, and cytoskeletal organization. Importantly, several clinically approved agonists have been shown to target this receptor. This study aimed to examine NISCH expression in PDAC and the effects of its agonists with the intent of drug repurposing. NISCH was expressed in PDAC tumor tissue, in both the epithelial and stromal compartments of tumors, and higher NISCH expression was associated with longer patient survival. Out of the three tested NISCH agonists, moxonidine, clonidine and rilmenidine, rilmenidine was the only one affecting cancer cell viability and at high doses induced cancer cell apoptosis. Transcriptome analysis of rilmenidine-treated PDAC cells revealed changes associated with cytoskeletal organization, translating into decreased adhesion and migration in vitro. In cancer-associated fibroblasts (CAFs), rilmenidine treatment decreased the expression of activation markers and limited cancer cell-CAF cytokine communication in the co-culture. Ultimately, in the in vivo tumor xenograft zebrafish model, rilmenidine reduced the metastatic spread of pancreatic cancer cells. Our results suggest that the NISCH agonist rilmenidine is a promising candidate for drug repurposing as an antimetastatic agent in PDAC, and that NISCH can be a potential target for the development of new PDAC therapeutics.<\/jats:p>","DOI":"10.3390\/cells15111032","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:08:07Z","timestamp":1780510087000},"page":"1032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing Rilmenidine as a Potential Antimetastatic Therapy Targeting Nischarin in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Kristina","family":"\u017divi\u0107","sequence":"first","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-562X","authenticated-orcid":false,"given":"Marijana","family":"Pavlovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-3559","authenticated-orcid":false,"given":"Marija","family":"Ostoji\u0107","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2262-8726","authenticated-orcid":false,"given":"Danijel","family":"Galun","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Belgrade, 11000 Belgrade, Serbia"},{"name":"HPB Unit, Clinic for Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar","family":"Pavi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9840-6970","authenticated-orcid":false,"given":"Tatjana","family":"Srdi\u0107-Raji\u0107","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-8682","authenticated-orcid":false,"given":"Jelena","family":"Grahovac","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer Statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sally, \u00c1., McGowan, R., Finn, K., and Moran, B.M. (2022). Current and Future Therapies for Pancreatic Ductal Adenocarcinoma. Cancers, 14.","DOI":"10.3390\/cancers14102417"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1016\/j.cell.2023.02.014","article-title":"Pancreatic Cancer: Advances and Challenges","volume":"186","author":"Halbrook","year":"2023","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2129884","DOI":"10.1080\/08941939.2022.2129884","article-title":"Pancreatic Cancer: A Review of Current Treatment and Novel Therapies","volume":"36","author":"Kolbeinsson","year":"2023","journal-title":"J. Investig. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1097\/SLA.0000000000004147","article-title":"Actual Five-Year Survival After Upfront Resection for Pancreatic Ductal Adenocarcinoma Who Beats the Odds?","volume":"275","author":"Strobel","year":"2022","journal-title":"Ann. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.cell.2011.11.025","article-title":"EMT and Dissemination Precede Pancreatic Tumor Formation","volume":"148","author":"Rhim","year":"2012","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/nature09515","article-title":"Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer","volume":"467","author":"Yachida","year":"2010","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1084\/jem.20162024","article-title":"Distinct Populations of Inflammatory Fibroblasts and Myofibroblasts in Pancreatic Cancer","volume":"214","author":"Biffi","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Joshi, R.S., Kanugula, S.S., Sudhir, S., Pereira, M.P., Jain, S., and Aghi, M.K. (2021). The Role of Cancer-Associated Fibroblasts in Tumor Progression. Cancers, 13.","DOI":"10.3390\/cancers13061399"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, T., Zhou, L., Li, D., Andl, T., and Zhang, Y. (2019). Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00060"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1042\/BST20160387","article-title":"Cancer-Associated Fibroblasts Modulate Growth Factor Signaling and Extracellular Matrix Remodeling to Regulate Tumor Metastasis","volume":"45","author":"Erdogan","year":"2017","journal-title":"Biochem. Soc. Trans."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1186\/s13046-022-02524-w","article-title":"The Importance of Being CAFs (in Cancer Resistance to Targeted Therapies)","volume":"41","author":"Rizzolio","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1083\/jcb.151.6.1141","article-title":"Nischarin, a Novel Protein That Interacts with the Integrin A5 Subunit and Inhibits Cell Migration","volume":"151","author":"Alahari","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1089\/10445490050043290","article-title":"Imidazoline Receptor Antisera-Selected (IRAS) CDNA: Cloning and Characterization","volume":"19","author":"Piletz","year":"2000","journal-title":"DNA Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/s41388-021-02150-4","article-title":"Role of Nischarin in the Pathology of Diseases: A Special Emphasis on Breast Cancer","volume":"41","author":"Okpechi","year":"2022","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ostoji\u0107, M., \u0110uri\u0107, A., \u017divi\u0107, K., and Grahovac, J. (2024). Analysis of the Nischarin Expression across Human Tumor Types Reveals Its Context-Dependent Role and a Potential as a Target for Drug Repurposing in Oncology. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0299685"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1124\/pr.118.016311","article-title":"Imidazoline Receptor System: The Past, the Present, and the Future","volume":"72","author":"Bousquet","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"298","DOI":"10.2174\/1386207311316040004","article-title":"Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study","volume":"16","author":"Nikolic","year":"2013","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.1158\/0008-5472.CAN-23-0816","article-title":"Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in CBioPortal","volume":"83","author":"Kundra","year":"2023","journal-title":"Cancer Res."},{"key":"ref_20","unstructured":"Cancer Genome Atlas Research Network (2017). Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell, 32, 185\u2013203."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic Analyses Identify Molecular Subtypes of Pancreatic Cancer","volume":"531","author":"Bailey","year":"2016","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ccr.2009.07.016","article-title":"FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt","volume":"16","author":"Pei","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1158\/0008-5472.CAN-15-2841","article-title":"A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2","volume":"76","author":"Yang","year":"2016","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: Archive for Functional Genomics Data Sets\u2014Update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1136\/gutjnl-2018-317706","article-title":"Experimental Microdissection Enables Functional Harmonisation of Pancreatic Cancer Subtypes","volume":"68","author":"Maurer","year":"2019","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Tissue-Based Map of the Human Proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1093\/nar\/gkz430","article-title":"GEPIA2: An Enhanced Web Server for Large-Scale Expression Profiling and Interactive Analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neo.2022.01.001","article-title":"UALCAN: An Update to the Integrated Cancer Data Analysis Platform","volume":"25","author":"Chandrashekar","year":"2022","journal-title":"Neoplasia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for Analysis of Tumor-Infiltrating Immune Cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s00109-023-02339-y","article-title":"Nischarin Expression May Have Differing Roles in Male and Female Melanoma Patients","volume":"101","author":"Grahovac","year":"2023","journal-title":"J. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1590\/S0100-879X2006000700009","article-title":"Detection of Multiple Mycoplasma Infection in Cell Cultures by PCR","volume":"39","author":"Timenetsky","year":"2006","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0016-5085(98)70209-4","article-title":"Identification, Culture, and Characterization of Pancreatic Stellate Cells in Rats and Humans","volume":"115","author":"Bachem","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/978-1-61779-854-2_8","article-title":"Assessment of Gelatinases (MMP-2 and MMP-9) by Gelatin Zymography","volume":"Volume 878","author":"Toth","year":"2012","journal-title":"Metastasis Research Protocols"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijbiomac.2020.01.033","article-title":"Lectin from Laetiporus Sulphureus Effectively Inhibits Angiogenesis and Tumor Development in the Zebra Fish Xenograft Models of Colorectal Carcinoma and Melanoma","volume":"148","author":"Petrovic","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1134\/S1022795408020142","article-title":"Human Chromosome 3P Regions of Putative Tumor-Suppressor Genes in Renal, Breast, and Ovarian Carcinomas","volume":"44","author":"Loginov","year":"2008","journal-title":"Russ. J. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1038\/sj.bjc.6603088","article-title":"The A2\u03b21 Integrin Mediates the Malignant Phenotype on Type I Collagen in Pancreatic Cancer Cell Lines","volume":"94","author":"Grzesiak","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1091\/mbc.9.7.1863","article-title":"Activation of Rac and Cdc42 by Integrins Mediates Cell Spreading","volume":"9","author":"Price","year":"1998","journal-title":"Mol. Biol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/12068","article-title":"Rac Regulates Phosphorylation of the Myosin-II Heavy Chain, Actinomyosin Disassembly and Cell Spreading","volume":"1","author":"Kain","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0014-4827(03)00233-7","article-title":"Nischarin Inhibits Rac Induced Migration and Invasion of Epithelial Cells by Affecting Signaling Cascades Involving PAK","volume":"288","author":"Alahari","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kim, S.K., Jang, S.D., Kim, H., Chung, S., Park, J.K., and Kuh, H.J. (2020). Phenotypic Heterogeneity and Plasticity of Cancer Cell Migration in a Pancreatic Tumor Three-Dimensional Culture Model. Cancers, 12.","DOI":"10.3390\/cancers12051305"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"216859","DOI":"10.1016\/j.canlet.2024.216859","article-title":"Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Therapy: Challenges and Opportunities","volume":"591","author":"Qin","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1158\/2159-8290.CD-18-0710","article-title":"IL-1-Induced JAK\/STAT Signaling Is Antagonized by TGF-\u03b2 to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma","volume":"9","author":"Biffi","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.cell.2019.05.012","article-title":"Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer","volume":"178","author":"Ligorio","year":"2019","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1158\/2159-8290.CD-19-0094","article-title":"Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts","volume":"9","author":"Elyada","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_47","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA. Cancer J. Clin."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1097\/SLA.0000000000002234","article-title":"Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma","volume":"267","author":"Groot","year":"2018","journal-title":"Ann. Surg."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2741\/3722","article-title":"Epithelial and Mesenchymal Phenotypic Switchings Modulate Cell Motility in Metastasis","volume":"16","author":"Wells","year":"2011","journal-title":"Front. Biosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.tips.2013.03.001","article-title":"Targeting Tumor Cell Motility as a Strategy against Invasion and Metastasis","volume":"34","author":"Wells","year":"2014","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e22708","DOI":"10.1002\/jbt.22708","article-title":"Enriched Cancer Stem Cells, Dense Stroma, and Cold Immunity: Interrelated Events in Pancreatic Cancer","volume":"35","author":"Mortezaee","year":"2021","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"16833","DOI":"10.1074\/jbc.M117.784256","article-title":"Nischarin Inhibition Alters Energy Metabolism by Activating AMP-Activated Protein Kinase","volume":"292","author":"Dong","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.ejps.2015.10.017","article-title":"Rilmenidine Suppresses Proliferation and Promotes Apoptosis via the Mitochondrial Pathway in Human Leukemic K562 Cells","volume":"81","author":"Nikolic","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12943-018-0764-6","article-title":"Nischarin Regulates Focal Adhesion and Invadopodia Formation in Breast Cancer Cells","volume":"17","author":"Maziveyi","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/ncb2548","article-title":"Classifying Collective Cancer Cell Invasion","volume":"14","author":"Friedl","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41556-017-0012-0","article-title":"Mechanoreciprocity in Cell Migration","volume":"20","author":"Storm","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.freeradbiomed.2025.11.013","article-title":"Redox Regulation of Cell Migration via Nischarin S-Glutathionylation","volume":"243","author":"Shivamadhu","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1158\/1541-7786.MCR-07-2167","article-title":"Zebrafish as a Cancer Model","volume":"6","author":"Feitsma","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-0716-1350-4_1","article-title":"Cancer Cell Invasion and Metastasis in Zebrafish Models (Danio rerio)","volume":"Volume 2294","author":"Roth","year":"2022","journal-title":"Metastasis"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1016\/j.celrep.2019.07.102","article-title":"Metastatic Tumor Cells Exploit Their Adhesion Repertoire to Counteract Shear Forces during Intravascular Arrest","volume":"28","author":"Osmani","year":"2019","journal-title":"Cell Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.semcancer.2021.03.006","article-title":"Heterogeneity and Plasticity of Cancer-Associated Fibroblasts in the Pancreatic Tumor Microenvironment","volume":"82","author":"Boyd","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.suronc.2015.05.002","article-title":"The Role of Pancreatic Stellate Cells in Pancreatic Cancer","volume":"24","author":"Moir","year":"2015","journal-title":"Surg. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"262","DOI":"10.21037\/atm-22-407","article-title":"Subpopulations of Cancer-Associated Fibroblasts Link the Prognosis and Metabolic Features of Pancreatic Ductal Adenocarcinoma","volume":"10","author":"Hu","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1158\/2159-8290.CD-20-1484","article-title":"Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL-6 Mediated Therapy Resistance in Pancreatic Cancer","volume":"12","author":"McAndrews","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1158\/0008-5472.CAN-15-2973","article-title":"FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling","volume":"74","author":"Yang","year":"2016","journal-title":"Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1042\/CS20191211","article-title":"Emerging Roles for the IL-6 Family of Cytokines in Pancreatic Cancer","volume":"134","author":"Griffin","year":"2020","journal-title":"Clin. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"65982","DOI":"10.18632\/oncotarget.11786","article-title":"Pancreatic Stellate Cell Secreted IL-6 Stimulates STAT3 Dependent Invasiveness of Pancreatic Intraepithelial Neoplasia and Cancer Cells","volume":"7","author":"Nagathihalli","year":"2016","journal-title":"Oncotarget"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s41467-017-01236-6","article-title":"Activation of STAT3 Integrates Common Profibrotic Pathways to Promote Fibroblast Activation and Tissue Fibrosis","volume":"8","author":"Chakraborty","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/s41419-020-03168-4","article-title":"Stroma Secreted IL6 Selects for \u201cStem-like\u201d Population and Alters Pancreatic Tumor Microenvironment by Reprogramming Metabolic Pathways","volume":"11","author":"Kesh","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/0002-9149(88)90467-5","article-title":"Dose and Concentration-Effect Relations for Rilmenidine","volume":"61","author":"Dollery","year":"1988","journal-title":"Am. J. Cardiol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Luengo, A., Sullivan, L.B., and Heiden, V.G.V. (2014). Understanding the Complex-I-Ty of Metformin Action: Limiting Mitochondrial Respiration to Improve Cancer Therapy. BMC Biol., 12.","DOI":"10.1186\/s12915-014-0082-4"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.cmet.2016.09.006","article-title":"Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin","volume":"24","author":"Gui","year":"2016","journal-title":"Cell Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e13774","DOI":"10.1111\/acel.13774","article-title":"Rilmenidine Extends Lifespan and Healthspan in Caenorhabditis Elegans via a Nischarin I1-Imidazoline Receptor","volume":"22","author":"Bennett","year":"2023","journal-title":"Aging Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"105359","DOI":"10.1016\/j.nbd.2021.105359","article-title":"Stimulation of MTOR-Independent Autophagy and Mitophagy by Rilmenidine Exacerbates the Phenotype of Transgenic TDP-43 Mice","volume":"154","author":"Perera","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"122841","DOI":"10.1016\/j.ijpharm.2023.122841","article-title":"Brain-Targeted Delivery of Losartan through Functionalized Liposomal Nanoparticles for Management of Neurogenic Hypertension","volume":"637","author":"Lamptey","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/10837450.2016.1265553","article-title":"Losartan Loaded Liposomes Improve the Antitumor Efficacy of Liposomal Paclitaxel Modified with PH Sensitive Peptides by Inhibition of Collagen in Breast Cancer","volume":"23","author":"Xia","year":"2018","journal-title":"Pharm. Dev. Technol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/11\/1032\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T02:52:02Z","timestamp":1780887122000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/11\/1032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":77,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cells15111032"],"URL":"https:\/\/doi.org\/10.3390\/cells15111032","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]}}}