{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T12:18:45Z","timestamp":1774441125137,"version":"3.50.1"},"reference-count":90,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010519","name":"LSU-LCMC Cancer Center","doi-asserted-by":"publisher","award":["#14976036TN"],"award-info":[{"award-number":["#14976036TN"]}],"id":[{"id":"10.13039\/100010519","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a five-year survival rate of approximately 13%. Patients with PDAC also have an elevated incidence of venous thromboembolism (VTE), despite prophylactic anticoagulation. Thus, there is an urgent need for therapeutic strategies that target tumor progression and hypercoagulability. Protein S (PS), a physiological anticoagulant encoded by the PROS1 gene, has recently been shown to inhibit PDAC growth in preclinical models. To further examine the physiological relevance of intratumoral PS in PDAC, we performed a meta-analysis of four independent PDAC patient cohorts obtained from cBioPortal. Patients were stratified based on low versus high intratumoral PROS1 expression based on below- and above-average mean expression, overall survival, and gene expression of select pro-growth genes, implementing a fixed-effects model. High intratumoral PROS1 expression was associated with a 41.8% reduction in the risk of death compared with low PROS1 expression (pooled hazard ratio = 0.581) within 30 months of diagnosis from survival data in three cohorts. Elevated PROS1 expression correlated with marked downregulation of key genes implicated in PDAC invasion and metastasis, including MMP2 and SNAI2, in all four cohorts. Collectively, these findings suggest that PROS1 is a potential prognostic biomarker and molecular regulator in PDAC and thus support further investigation into the dual role of PS in tumor progression.<\/jats:p>","DOI":"10.3390\/ijms27072964","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T09:11:14Z","timestamp":1774429874000},"page":"2964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High Intratumoral PROS1 Expression Correlates with Improved Survival and Is Associated with Suppressed Oncogenic Signaling in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7419-9241","authenticated-orcid":false,"given":"Teagan","family":"Prouse","sequence":"first","affiliation":[{"name":"Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1727-7220","authenticated-orcid":false,"given":"Rinku","family":"Majumder","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1831-664X","authenticated-orcid":false,"given":"Samarpan","family":"Majumder","sequence":"additional","affiliation":[{"name":"Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","first-page":"e72816","article-title":"Unraveling Pancreatic Cancer: Epidemiology, Risk Factors, and Global Trends","volume":"16","author":"Qadir","year":"2024","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.3748\/wjg.v27.i27.4298","article-title":"Pancreatic cancer: A review of epidemiology, trend, and risk factors","volume":"27","author":"Hu","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14740\/wjon1166","article-title":"Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4698","DOI":"10.3748\/wjg.v28.i32.4698","article-title":"International patterns in incidence and mortality trends of pancreatic cancer in the last three decades: A joinpoint regression analysis","volume":"28","author":"Ilic","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_5","unstructured":"American Cancer Society (2025). Cancer Facts & Figures 2025, American Cancer Society."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1053\/j.gastro.2023.02.012","article-title":"Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention","volume":"164","author":"Stoffel","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dallavalle, S., Campagnoli, G., Pastena, P., Martinino, A., Schiliro, D., and Giovinazzo, F. (2024). New Frontiers in Pancreatic Cancer Management: Current Treatment Options and the Emerging Role of Neoadjuvant Therapy. Medicina, 60.","DOI":"10.3390\/medicina60071070"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/S0140-6736(25)00261-2","article-title":"Pancreatic cancer","volume":"405","author":"Stoop","year":"2025","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Li, W., Niu, J., Fan, Z., Li, X., and Zhang, H. (2025). Reprogramming of glucose metabolism in pancreatic cancer: Mechanisms, implications, and therapeutic perspectives. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1586959"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lauria, G., Curcio, R., Lunetti, P., Tiziani, S., Coppola, V., Dolce, V., Fiermonte, G., and Ahmed, A. (2023). Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review. Cancers, 15.","DOI":"10.3390\/cancers15020411"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40170-020-00226-5","article-title":"Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase","volume":"8","author":"Sharma","year":"2020","journal-title":"Cancer Metab."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Palamaris, K., Felekouras, E., and Sakellariou, S. (2021). Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance. Cancers, 13.","DOI":"10.3390\/cancers13215532"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e20240766","DOI":"10.1084\/jem.20240766","article-title":"NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer","volume":"221","author":"Deng","year":"2024","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115561","DOI":"10.1016\/j.ejca.2025.115561","article-title":"Regulation of epithelial-mesenchymal plasticity in pancreatic ductal adenocarcinoma: Role of key molecules in tumor differentiation and therapy","volume":"225","author":"Ling","year":"2025","journal-title":"Eur. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1053\/j.gastro.2019.12.009","article-title":"Incidence of Venous Thromboembolism in Patients with Newly Diagnosed Pancreatic Cancer and Factors Associated with Outcomes","volume":"158","author":"Frere","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.pan.2024.06.008","article-title":"Venous thromboembolism in patients with pancreatic adenocarcinoma: Disease burden and initiation of ambulatory thromboprophylaxis","volume":"24","author":"Heffley","year":"2024","journal-title":"Pancreatology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Frere, C., Gourgou, S., Winter, A., Gauthier, L., Canivet, C., Crichi, B., Marjanovic, Z., Yannoutsos, A., Bensaoula, O., and Buscail, L. (2025). Risk Assessment Models for Predicting Venous Thromboembolism in Patients with Pancreatic Cancer. Cancers, 17.","DOI":"10.3390\/cancers17040597"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Willems, R.A.L., Michiels, N., Lanting, V.R., Bouwense, S., van den Broek, B.L.J., Graus, M., Klok, F.A., Groot Koerkamp, B., de Laat, B., and Roest, M. (2023). Venous Thromboembolism and Primary Thromboprophylaxis in Perioperative Pancreatic Cancer Care. Cancers, 15.","DOI":"10.3390\/cancers15143546"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e334","DOI":"10.1016\/S1470-2045(22)00160-7","article-title":"2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19","volume":"23","author":"Farge","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1200\/JCO.19.01461","article-title":"Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Clinical Practice Guideline Update","volume":"38","author":"Key","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Gornicki, T., Buldys, K., Zielinska, D., and Chabowski, M. (2023). Direct-Acting Oral Anticoagulant Therapy in Cancer Patients-A Review. Cancers, 15.","DOI":"10.3390\/cancers15102697"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1111\/jth.14604","article-title":"Rivaroxaban does not affect growth of human pancreatic tumors in mice","volume":"17","author":"Maqsood","year":"2019","journal-title":"J. Thromb. Haemost."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1055\/s-2007-1004415","article-title":"Protein S and the regulation of activated protein C","volume":"10","author":"Walker","year":"1984","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11128","DOI":"10.1016\/S0021-9258(19)68566-2","article-title":"Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation","volume":"256","author":"Walker","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1161\/01.ATV.0000168421.13467.82","article-title":"Regulation of blood coagulation by the protein C anticoagulant pathway: Novel insights into structure-function relationships and molecular recognition","volume":"25","author":"Dahlback","year":"2005","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1111\/j.1538-7836.2008.02980.x","article-title":"Protein S enhances the tissue factor pathway inhibitor inhibition of factor Xa but not its inhibition of factor VIIa-tissue factor","volume":"6","author":"Ndonwi","year":"2008","journal-title":"J. Thromb. Haemost."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1161\/ATVBAHA.108.177436","article-title":"Protein S as cofactor for TFPI","volume":"29","author":"Hackeng","year":"2009","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3106","DOI":"10.1073\/pnas.0504240103","article-title":"Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor","volume":"103","author":"Hackeng","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1161\/ATVBAHA.112.250928","article-title":"Inhibition of intrinsic Xase by protein S: A novel regulatory role of protein S independent of activated protein C","volume":"32","author":"Chattopadhyay","year":"2012","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.thromres.2018.08.018","article-title":"Padua FIXa resistance to Protein S and a potential therapy for hyperactive FIXa","volume":"170","author":"Plautz","year":"2018","journal-title":"Thromb. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1161\/ATVBAHA.117.310588","article-title":"Anticoagulant Protein S Targets the Factor IXa Heparin-Binding Exosite to Prevent Thrombosis","volume":"38","author":"Plautz","year":"2018","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1182\/blood-2018-04-841585","article-title":"Hypoxia downregulates protein S expression","volume":"132","author":"Pilli","year":"2018","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Prouse, T., Majumder, S., and Majumder, R. (2024). Functions of TAM Receptors and Ligands Protein S and Gas6 in Atherosclerosis and Cardiovascular Disease. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202410.0083.v1"},{"key":"ref_34","first-page":"1322","article-title":"Modulation of protein S and growth arrest specific 6 protein signaling inhibits pancreatic cancer cell survival and proliferation","volume":"44","author":"Pilli","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109233","DOI":"10.1016\/j.thromres.2024.109233","article-title":"Exogenous Protein S inhibits pancreatic ductal adenocarcinoma","volume":"245","author":"Prouse","year":"2025","journal-title":"Thromb. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1002\/1097-0142(19921015)70:8<2067::AID-CNCR2820700809>3.0.CO;2-A","article-title":"Coagulation inhibition and activation in pancreatic cancer. Changes during progress of disease","volume":"70","author":"Lindahl","year":"1992","journal-title":"Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.7150\/jca.72161","article-title":"GLUT1 Regulates the Tumor Immune Microenvironment and Promotes Tumor Metastasis in Pancreatic Adenocarcinoma via ncRNA-mediated Network","volume":"13","author":"Li","year":"2022","journal-title":"J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1111\/cas.16204","article-title":"Hexokinase 2 nonmetabolic function-mediated phosphorylation of IkappaBalpha enhances pancreatic ductal adenocarcinoma progression","volume":"115","author":"Tong","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1016\/j.csbj.2020.09.023","article-title":"TGIF1-Twist1 axis in pancreatic ductal adenocarcinoma","volume":"18","author":"Razzaque","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_40","first-page":"173","article-title":"Role of Notch signaling pathway in pancreatic cancer","volume":"7","author":"Gao","year":"2017","journal-title":"Am. J. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1158\/1078-0432.CCR-05-2387","article-title":"N-cadherin as a novel prognostic marker of progression in superficial urothelial tumors","volume":"12","author":"Lascombe","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e153242","DOI":"10.1172\/jci.insight.153242","article-title":"Targeting TNF-alpha-producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling","volume":"7","author":"Dixit","year":"2022","journal-title":"JCI Insight"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Principe, D.R., Timbers, K.E., Atia, L.G., Koch, R.M., and Rana, A. (2021). TGFbeta Signaling in the Pancreatic Tumor Microenvironment. Cancers, 13.","DOI":"10.3390\/cancers13205086"},{"key":"ref_44","first-page":"7075","article-title":"Hypoxia-inducible expression of tumor-associated carbonic anhydrases","volume":"60","author":"Wykoff","year":"2000","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1016\/j.bbamcr.2017.05.010","article-title":"Matrix metalloproteinases as regulators of inflammatory processes","volume":"1864","author":"Fingleton","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/wrr.12717","article-title":"Metalloproteinases in chronic and acute wounds: A systematic review and meta-analysis","volume":"27","year":"2019","journal-title":"Wound Repair Regen."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4987","DOI":"10.1111\/cas.15162","article-title":"SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2","volume":"112","author":"Masuo","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Chen, J.S., Hung, C.Y., Chang, H., Liu, C.T., Chen, Y.Y., Lu, C.H., Chang, P.H., Hung, Y.S., and Chou, W.C. (2018). Venous Thromboembolism in Asian Patients with Pancreatic Cancer Following Palliative Chemotherapy: Low Incidence but a Negative Prognosticator for Those with Early Onset. Cancers, 10.","DOI":"10.3390\/cancers10120501"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2174\/0113894501335877240926101134","article-title":"Envisioning Glucose Transporters (GLUTs and SGLTs) as Novel Intervention against Cancer: Drug Discovery Perspective and Targeting Approach","volume":"26","author":"Shafi","year":"2025","journal-title":"Curr. Drug Targets"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Infantino, V., Santarsiero, A., Convertini, P., Todisco, S., and Iacobazzi, V. (2021). Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115703"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/ncb1724","article-title":"p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation","volume":"10","author":"Kawauchi","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1038\/onc.2015.306","article-title":"Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer","volume":"35","author":"Zhang","year":"2016","journal-title":"Oncogene"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Tremblay, I., Pare, E., Arsenault, D., Douziech, M., and Boucher, M.J. (2013). The MEK\/ERK pathway promotes NOTCH signalling in pancreatic cancer cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0085502"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1136\/annrheumdis-2015-208420","article-title":"Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis","volume":"75","author":"Lin","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.3390\/cancers3033676","article-title":"The many faces of wnt and pancreatic ductal adenocarcinoma oncogenesis","volume":"3","author":"Weekes","year":"2011","journal-title":"Cancers"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1083\/jcb.201008173","article-title":"Evolution: Structural and functional diversity of cadherin at the adherens junction","volume":"193","author":"Oda","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.18632\/oncotarget.1875","article-title":"Epigenetic plasticity: A central regulator of epithelial-to-mesenchymal transition in cancer","volume":"5","author":"Bedi","year":"2014","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s43556-022-00109-9","article-title":"TGF-beta signal transduction: Biology, function and therapy for diseases","volume":"3","author":"Tie","year":"2022","journal-title":"Mol. Biomed."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/sj.emboj.7600069","article-title":"Integration of TGF-beta\/Smad and Jagged1\/Notch signalling in epithelial-to-mesenchymal transition","volume":"23","author":"Zavadil","year":"2004","journal-title":"EMBO J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s10555-019-09799-0","article-title":"The role of carbonic anhydrase IX in cancer development: Links to hypoxia, acidosis, and beyond","volume":"38","author":"Pastorekova","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_61","first-page":"2877","article-title":"Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment","volume":"9","author":"Pastorek","year":"1994","journal-title":"Oncogene"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.febslet.2004.10.043","article-title":"Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH","volume":"577","author":"Svastova","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/s41416-018-0216-5","article-title":"Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo","volume":"119","author":"Lee","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.yexcr.2018.03.020","article-title":"HIF-dependent and reversible nucleosome disassembly in hypoxia-inducible gene promoters","volume":"366","author":"Suzuki","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/nri3499","article-title":"Metalloproteinases and their natural inhibitors in inflammation and immunity","volume":"13","author":"Khokha","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Vo, H.V.T., Kim, N., and Lee, H.J. (2025). Vitamin Bs as Potent Anticancer Agents through MMP-2\/9 Regulation. Front. Biosci., 30.","DOI":"10.31083\/FBL24072"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1161\/01.ATV.0000209518.58252.17","article-title":"Pericellular proteases in angiogenesis and vasculogenesis","volume":"26","author":"Engelse","year":"2006","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1177\/153537020623100103","article-title":"Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis","volume":"231","author":"Ii","year":"2006","journal-title":"Exp. Biol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s10585-009-9245-z","article-title":"Transient RNA silencing of tissue factor pathway inhibitor-2 modulates lung cancer cell invasion","volume":"26","author":"Iochmann","year":"2009","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1042\/BST20210640","article-title":"MMP-7 marks severe pancreatic cancer and alters tumor cell signaling by proteolytic release of ectodomains","volume":"50","year":"2022","journal-title":"Biochem. Soc. Trans."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1242\/dev.01907","article-title":"The Snail genes as inducers of cell movement and survival: Implications in development and cancer","volume":"132","author":"Nieto","year":"2005","journal-title":"Development"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhang, D., Jiang, Z., Hu, J., Sun, X., Zheng, Y., and Shen, Y. (2023). Comprehensively prognostic and immunological analysis of snail family transcriptional repressor 2 in pan-cancer and identification in pancreatic carcinoma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1117585"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Di Santo, R., Niccolini, B., Rosa, E., De Spirito, M., Pizzolante, F., Pitocco, D., Tartaglione, L., Rizzi, A., Basile, U., and Petito, V. (2025). Artificial Intelligence for Liquid Biopsy: FTIR Spectroscopy and Autoencoder-Based Detection of Cancer Biomarkers in Extracellular Vesicles. Cells, 14.","DOI":"10.3390\/cells14231909"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"123346","DOI":"10.1016\/j.saa.2023.123346","article-title":"Advancements in Mid-Infrared spectroscopy of extracellular vesicles","volume":"305","author":"Niccolini","year":"2024","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e099488","DOI":"10.1136\/bmjopen-2025-099488","article-title":"Impact of race, sex and age on the probability of pancreatic cancer among patients with newly diagnosed diabetes in a claims-based cohort","volume":"15","author":"Afghani","year":"2025","journal-title":"BMJ Open"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Pijnappel, E.N., Schuurman, M., Wagner, A.D., de Vos-Geelen, J., van der Geest, L.G.M., de Groot, J.B., Koerkamp, B.G., de Hingh, I., Homs, M.Y.V., and Creemers, G.J. (2022). Sex, Gender and Age Differences in Treatment Allocation and Survival of Patients with Metastatic Pancreatic Cancer: A Nationwide Study. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.839779"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"114117","DOI":"10.1016\/j.ejca.2024.114117","article-title":"Gender differences in tumor characteristics, treatment allocation and survival in stage I-III pancreatic cancer: A nationwide study","volume":"206","author":"Gehrels","year":"2024","journal-title":"Eur. J. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/jrsm.1201","article-title":"Meta-analysis of prognostic studies for a biomarker with a study-specific cutoff value","volume":"7","author":"Sadashima","year":"2016","journal-title":"Res. Synth. Methods"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Hellwig, B., Hengstler, J.G., Schmidt, M., Gehrmann, M.C., Schormann, W., and Rahnenfuhrer, J. (2010). Comparison of scores for bimodality of gene expression distributions and genome-wide evaluation of the prognostic relevance of high-scoring genes. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-276"},{"key":"ref_81","first-page":"e70035","article-title":"Advances in pancreatic cancer early diagnosis, prevention, and treatment: The past, the present, and the future","volume":"76","author":"Mannucci","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"103","DOI":"10.4137\/CIN.S11496","article-title":"Prognostic estimator of survival for patients with localized and extended pancreatic ductal adenocarcinoma","volume":"12","author":"Gleason","year":"2013","journal-title":"Cancer Inform."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1467-985X.2008.00552.x","article-title":"A re-evaluation of random-effects meta-analysis","volume":"172","author":"Higgins","year":"2009","journal-title":"J. R. Stat. Soc. Ser. A Stat. Soc."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"IntHout, J., Ioannidis, J.P., and Borm, G.F. (2014). The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-25"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"(2015). von Hippel, P.T. The heterogeneity statistic I(2) can be biased in small meta-analyses. BMC Med. Res. Methodol., 15.","DOI":"10.1186\/s12874-015-0024-z"},{"key":"ref_86","unstructured":"Higgins, J., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M., and Welch, V. (2022). Analysing data and undertaking meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions; The Cochrane Collaboration, John Wiley & Sons."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/jrsm.12","article-title":"A basic introduction to fixed-effect and random-effects models for meta-analysis","volume":"1","author":"Borenstein","year":"2010","journal-title":"Res. Synth. Methods"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.tjem.2018.08.001","article-title":"User\u2019s guide to correlation coefficients","volume":"18","author":"Akoglu","year":"2018","journal-title":"Turk. J. Emerg. Med."},{"key":"ref_89","first-page":"69","article-title":"Statistics corner: A guide to appropriate use of correlation coefficient in medical research","volume":"24","author":"Mukaka","year":"2012","journal-title":"Malawi Med. J."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"McKenzie, A.T., Katsyv, I., Song, W.M., Wang, M., and Zhang, B. (2016). DGCA: A comprehensive R package for Differential Gene Correlation Analysis. BMC Syst. Biol., 10.","DOI":"10.1186\/s12918-016-0349-1"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/2964\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T09:20:14Z","timestamp":1774430414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/2964"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":90,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27072964"],"URL":"https:\/\/doi.org\/10.3390\/ijms27072964","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]}}}