{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:50:27Z","timestamp":1790801427490,"version":"4.1.0"},"reference-count":80,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["R01CA277680"],"award-info":[{"award-number":["R01CA277680"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic cancer is characterized by an extensive fibrotic stroma largely driven by activated pancreatic stellate cells (PSCs)\/fibroblasts, which also function to support tumor growth and metastasis. Cholecystokinin-B receptors (CCK-BRs) are expressed on pancreatic stellate cells (PSCs) and have emerged as a key regulator of PSC activation and tumor-stromal interactions. We hypothesized that disrupting CCK-BR function shifts PSCs to a more quiescent phenotype and reduces their pro-fibrotic and tumor-supportive activity to decrease growth of pancreatic cancer. Murine PSCs were genetically engineered with CRISPR-Cas9 to knockout the CCK-BR. In a series of experiments, the role of the CCK-BR expression was evaluated on cell migration, proliferation, differentially expressed genes, molecular signaling pathways, and in co-culture with murine pancreatic cancer epithelial cells. Next, primary human pancreatic stellate cells were treated with proglumide, a CCK-BR antagonist, to study the effects of pharmacologic blockade of the CCK-BR on cellular signaling and proliferative pathways by RNA sequencing. Knockout of the CCK-BR led to significant decreases in PSC activation and the ability to stimulate growth of pancreatic cancer cells in co-culture. Both genetic knockdown and pharmacologic blockade of the CCK-BR downregulated genes implicated in fibrosis, proliferation, fibroblast activation, and tumorigenesis, while genes implicated in apoptosis and tumor suppression were upregulated. Flow cytometry showed increased apoptosis markers in CCK-BR-knockout cells compared to controls. These experiments combine transcriptomic profiling with functional validation to provide a comprehensive analysis of how targeting CCK-BR interrupts the cross-communication between cancer cells and fibroblasts. Blockade or downregulation of the CCK-BR on pancreatic fibroblasts may provide a strategy to disrupt oncogenic signaling pathways and reprogram the tumor microenvironment.<\/jats:p>","DOI":"10.3390\/ijms262311699","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T08:44:28Z","timestamp":1764751468000},"page":"11699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Downregulation of the CCK-B Receptor in Pancreatic Stellate Cells Blocks Molecular Proliferative Pathways and Increases Apoptosis to Decrease Pancreatic Cancer Growth In Vitro"],"prefix":"10.3390","volume":"26","author":[{"given":"Miranda","family":"Ortega","sequence":"first","affiliation":[{"name":"Departments of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Agena","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6864-9932","authenticated-orcid":false,"given":"Wenqiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1882-7909","authenticated-orcid":false,"given":"Sona","family":"Vasudevan","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayan","family":"Shivapurkar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariaelena","family":"Pierobon","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-4802","authenticated-orcid":false,"given":"Jill P.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1097\/MOG.0000000000000196","article-title":"Pancreatic stellate cell: Physiologic role, role in fibrosis and cancer","volume":"31","author":"Apte","year":"2015","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1152\/physrev.00048.2019","article-title":"Diversity and Biology of Cancer-Associated Fibroblasts","volume":"101","author":"Biffi","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.7150\/jca.38616","article-title":"Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer","volume":"11","author":"Jin","year":"2020","journal-title":"J. Cancer"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"e70788","DOI":"10.1002\/cam4.70788","article-title":"Fibrotic Fortresses and Therapeutic Frontiers: Pancreatic Stellate Cells and the Extracellular Matrix in Pancreatic Cancer","volume":"14","author":"Sigirli","year":"2025","journal-title":"Cancer Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.tranon.2017.04.009","article-title":"The Role of Fibroblasts in Pancreatic Cancer: Extracellular Matrix Versus Paracrine Factors","volume":"10","author":"Bolm","year":"2017","journal-title":"Transl. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.semcancer.2023.05.007","article-title":"Emerging role of pancreatic stellate cell-derived extracellular vesicles in pancreatic cancer","volume":"93","author":"Sarkar","year":"2023","journal-title":"Semin. Cancer Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s13105-022-00899-0","article-title":"The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis","volume":"79","author":"Barrera","year":"2023","journal-title":"J. Physiol. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.molmed.2023.03.002","article-title":"Fibroblasts in pancreatic cancer: Molecular and clinical perspectives","volume":"29","author":"Rebelo","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10732748221078470","DOI":"10.1177\/10732748221078470","article-title":"Cytokine Interaction with Cancer-Associated Fibroblasts in Esophageal Cancer","volume":"29","author":"Hassan","year":"2022","journal-title":"Cancer Control"},{"key":"ref_11","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_12","doi-asserted-by":"crossref","unstructured":"Ansardamavandi, A., and Tafazzoli-Shadpour, M. (2021). The functional cross talk between cancer cells and cancer associated fibroblasts from a cancer mechanics perspective. Biochim. Biophys. Acta Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2021.119103"},{"key":"ref_13","first-page":"8437","article-title":"Immune cells regulate matrix metalloproteinases to reshape the tumor microenvironment to affect the invasion, migration, and metastasis of pancreatic cancer","volume":"14","author":"Wang","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107750","DOI":"10.1016\/j.phrs.2025.107750","article-title":"MMP3 at the crossroads: Linking molecular pathways to disease diagnosis and therapy","volume":"216","author":"Jiang","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.neo.2016.06.003","article-title":"Profile of MMP and TIMP Expression in Human Pancreatic Stellate Cells: Regulation by IL-1alpha and TGFbeta and Implications for Migration of Pancreatic Cancer Cells","volume":"18","author":"Tjomsland","year":"2016","journal-title":"Neoplasia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1186\/s12967-025-06447-w","article-title":"Matrix metalloproteinase-driven epithelial-mesenchymal transition: Implications in health and disease","volume":"23","author":"Radisky","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Jolly, G., Duka, T., Shivapurkar, N., Chen, W., Bansal, S., Cheema, A., and Smith, J.P. (2023). Cholecystokinin Receptor Antagonist Induces Pancreatic Stellate Cell Plasticity Rendering the Tumor Microenvironment Less Oncogenic. Cancers, 15.","DOI":"10.3390\/cancers15102811"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Malchiodi, Z.X., Cao, H., Gay, M.D., Safronenka, A., Bansal, S., Tucker, R.D., Weinberg, B.A., Cheema, A., Shivapurkar, N., and Smith, J.P. (2021). Cholecystokinin Receptor Antagonist Improves Efficacy of Chemotherapy in Murine Models of Pancreatic Cancer by Altering the Tumor Microenvironment. Cancers, 13.","DOI":"10.3390\/cancers13194949"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Doneparthi, P.S., Cao, H., Chen, W., Dou, W., Fang, H.B., and Smith, J.P. (2025). Mechanistic Insights into Proglumide\u2019s Role in Immune Cell Efficacy and Response to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma. Cancers, 17.","DOI":"10.3390\/cancers17182998"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s00262-017-2077-9","article-title":"Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice","volume":"67","author":"Smith","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16120","DOI":"10.18632\/oncotarget.3878","article-title":"Leptin signaling enhances cell invasion and promotes the metastasis of human pancreatic cancer via increasing MMP-13 production","volume":"6","author":"Fan","year":"2015","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/1476-4598-13-130","article-title":"Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4\/ErbB2\/p38\/MEF2C-dependent mechanism","volume":"13","author":"Zhang","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1021\/acs.jproteome.4c00036","article-title":"Integrated Exploration of Epigenetic Dysregulation Reveals a Stemness\/EMT Subtype and MMP12 Linked to the Progression and Prognosis in Hepatocellular Carcinoma","volume":"23","author":"Zuo","year":"2024","journal-title":"J. Proteome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3797","DOI":"10.1038\/onc.2008.32","article-title":"p53 target gene AEN is a nuclear exonuclease required for p53-dependent apoptosis","volume":"27","author":"Kawase","year":"2008","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Shalaby, R., Flores-Romero, H., and Garcia-Saez, A.J. (2020). The Mysteries around the BCL-2 Family Member BOK. Biomolecules, 10.","DOI":"10.3390\/biom10121638"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3892\/or.2016.4793","article-title":"Protocadherin-10 acts as a tumor suppressor gene, and is frequently downregulated by promoter methylation in pancreatic cancer cells","volume":"36","author":"Qiu","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gasparini, G., Pellegatta, M., Crippa, S., Lena, M.S., Belfiori, G., Doglioni, C., Taveggia, C., and Falconi, M. (2019). Nerves and Pancreatic Cancer: New Insights into a Dangerous Relationship. Cancers, 11.","DOI":"10.3390\/cancers11070893"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Moore, L.L., Qu, D., Sureban, S., Mitchell, S., Pitts, K., Cooper, N., Fazili, J., Harty, R., Oseini, A., and Ding, K. (2024). From Inflammation to Oncogenesis: Tracing Serum DCLK1 and miRNA Signatures in Chronic Liver Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126481"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kagawa, K., Sato, S., Koyama, K., Imakura, T., Murakami, K., Yamashita, Y., Naito, N., Ogawa, H., Kawano, H., and Nishioka, Y. (2022). The lymphocyte-specific protein tyrosine kinase-specific inhibitor A-770041 attenuates lung fibrosis via the suppression of TGF-beta production in regulatory T-cells. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0275987"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11737","DOI":"10.7150\/thno.47717","article-title":"Glycogen synthase kinase-3beta: A promising candidate in the fight against fibrosis","volume":"10","author":"Zheng","year":"2020","journal-title":"Theranostics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1091\/mbc.e05-09-0869","article-title":"Protein kinase Czeta attenuates hypoxia-induced proliferation of fibroblasts by regulating MAP kinase phosphatase-1 expression","volume":"17","author":"Short","year":"2006","journal-title":"Mol. Biol. Cell."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"L722","DOI":"10.1152\/ajplung.00131.2017","article-title":"Distinct PKA regulatory subunits mediate PGE(2) inhibition of TGFbeta-1-stimulated collagen I translation and myofibroblast differentiation","volume":"313","author":"Wettlaufer","year":"2017","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Liu, J., Wang, F., and Luo, F. (2023). The Role of JAK\/STAT Pathway in Fibrotic Diseases: Molecular and Cellular Mechanisms. Biomolecules, 13.","DOI":"10.3390\/biom13010119"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1242\/jcs.115.13.2771","article-title":"Regulation of S33\/S37 phosphorylated beta-catenin in normal and transformed cells","volume":"115","author":"Sadot","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1053\/j.gastro.2011.05.041","article-title":"Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions","volume":"141","author":"Carriere","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1177\/1947601910397188","article-title":"Emerging roles for crk in human cancer","volume":"1","author":"Sriram","year":"2010","journal-title":"Genes Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S1097-2765(02)00689-5","article-title":"The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors","volume":"10","author":"Lax","year":"2002","journal-title":"Mol. Cell."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1007\/s00018-015-2112-y","article-title":"FOXO transcription factors in cancer development and therapy","volume":"73","author":"Demoulin","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3892\/ol.2024.14576","article-title":"Interference with ENO2 promotes ferroptosis and inhibits glycolysis in clear cell renal cell carcinoma by regulating Hippo-YAP1 signaling","volume":"28","author":"Li","year":"2024","journal-title":"Oncol. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"eabc6612","DOI":"10.1126\/scisignal.abc6612","article-title":"Emerging roles of PLCgamma1 in endothelial biology","volume":"14","author":"Chen","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"101","DOI":"10.7150\/ijms.98252","article-title":"Cadherin 23 is a prognostic marker of pancreatic cancer and promotes cell viability in floating culture conditions","volume":"22","author":"Zhen","year":"2025","journal-title":"Int. J. Med. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Baumann, A., Nier, A., Hernandez-Arriaga, A., Brandt, A., Lorenzo Pisarello, M.J., Jin, C.J., Pilar, E., Camarinha-Silva, A., Schattenberg, J.M., and Bergheim, I. (2021). Toll-like receptor 1 as a possible target in non-alcoholic fatty liver disease. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-97346-9"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"156504","DOI":"10.1016\/j.cyto.2024.156504","article-title":"Atypical chemokine receptors in cancer","volume":"176","author":"Samus","year":"2024","journal-title":"Cytokine"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bayly-Jones, C., Pang, S.S., Spicer, B.A., Whisstock, J.C., and Dunstone, M.A. (2020). Ancient but Not Forgotten: New Insights Into MPEG1, a Macrophage Perforin-Like Immune Effector. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.581906"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"107178","DOI":"10.1016\/j.phrs.2024.107178","article-title":"IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation","volume":"203","author":"Zhu","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Liu, Y., Ouyang, Y., Feng, Z., Jiang, Z., Ma, J., Zhou, X., Cai, C., Han, Y., Zeng, S., and Liu, S. (2023). RASGRP2 is a potential immune-related biomarker and regulates mitochondrial-dependent apoptosis in lung adenocarcinoma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1100231"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1158\/2159-8290.CD-20-1098","article-title":"PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability","volume":"11","author":"Pitarresi","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1177\/1535370216670541","article-title":"Tissue transglutaminase-1 promotes stemness and chemoresistance in gastric cancer cells by regulating Wnt\/beta-catenin signaling","volume":"242","author":"Huang","year":"2017","journal-title":"Exp. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1159\/000489374","article-title":"MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFbeta\/SMAD Signaling Pathway in Colorectal Cancer Metastasis","volume":"46","author":"Hu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"108429","DOI":"10.1016\/j.intimp.2021.108429","article-title":"TNFSF9 promotes metastasis of pancreatic cancer by regulating M2 polarization of macrophages through Src\/FAK\/p-Akt\/IL-1beta signaling","volume":"102","author":"Wu","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1172\/JCI60144","article-title":"Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis","volume":"122","author":"Hamidi","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/s41698-025-01017-1","article-title":"Genetic and oncogenic features of RASGRF fusions","volume":"9","author":"Das","year":"2025","journal-title":"NPJ Precis. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/MPA.0000000000000686","article-title":"Exosome-Mediated Intercellular Communication Between Stellate Cells and Cancer Cells in Pancreatic Ductal Adenocarcinoma","volume":"46","author":"Lugea","year":"2017","journal-title":"Pancreas"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12943-020-01255-w","article-title":"The potential roles of exosomes in pancreatic cancer initiation and metastasis","volume":"19","author":"Sun","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","article-title":"Safety and activity of anti-PD-L1 antibody in patients with advanced cancer","volume":"366","author":"Brahmer","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1097\/MOG.0b013e328363affe","article-title":"Deciphering the role of stroma in pancreatic cancer","volume":"29","author":"Waghray","year":"2013","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1053\/j.gastro.2012.12.042","article-title":"Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma","volume":"144","author":"Zheng","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1172\/JCI45817","article-title":"Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors","volume":"122","author":"Salmon","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"8429","DOI":"10.1074\/jbc.270.15.8429","article-title":"Novel gastrin receptors mediate mitogenic effects of gastrin and processing intermediates of gastrin on Swiss 3T3 fibroblasts. Absence of detectable cholecystokinin (CCK)-A and CCK-B receptors","volume":"270","author":"Singh","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"38905","DOI":"10.1074\/jbc.M110.125534","article-title":"CCK1 and CCK2 receptors are expressed on pancreatic stellate cells and induce collagen production","volume":"285","author":"Berna","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/00006676-200410000-00002","article-title":"Desmoplastic reaction in pancreatic cancer: Role of pancreatic stellate cells","volume":"29","author":"Apte","year":"2004","journal-title":"Pancreas"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1053\/j.gastro.2012.11.037","article-title":"A starring role for stellate cells in the pancreatic cancer microenvironment","volume":"144","author":"Apte","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1097\/MPA.0000000000000194","article-title":"Cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice","volume":"43","author":"Smith","year":"2014","journal-title":"Pancreas"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chan, Y.T., Wang, N., Tan, H.Y., Li, S., and Feng, Y. (2020). Targeting Hepatic Stellate Cells for the Treatment of Liver Fibrosis by Natural Products: Is It the Dawning of a New Era?. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00548"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/13543784.2020.1718106","article-title":"Targeting CCR2\/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: Opportunities and challenges","volume":"29","author":"Lefere","year":"2020","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.4161\/hv.34392","article-title":"Pancreatic cancer: Role of the immune system in cancer progression and vaccine-based immunotherapy","volume":"10","author":"Amedei","year":"2014","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4965","DOI":"10.1158\/0008-5472.CAN-13-0661","article-title":"Targeting the tumor microenvironment: From understanding pathways to effective clinical trials","volume":"73","author":"Fang","year":"2013","journal-title":"Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.ctrv.2013.11.005","article-title":"Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies","volume":"40","author":"Sideras","year":"2014","journal-title":"Cancer Treat. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s12094-015-1459-8","article-title":"Targeting the microenvironment of pancreatic cancer: Overcoming treatment barriers and improving local immune responses","volume":"18","author":"Strauss","year":"2016","journal-title":"Clin. Transl. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2848","DOI":"10.1158\/1078-0432.CCR-15-2010","article-title":"Phase Ib Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer","volume":"22","author":"Hingorani","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1200\/JCO.20.00590","article-title":"Randomized Phase III Trial of Pegvorhyaluronidase Alfa with Nab-Paclitaxel Plus Gemcitabine for Patients with Hyaluronan-High Metastatic Pancreatic Adenocarcinoma","volume":"38","author":"Van","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-1-4939-6990-6_4","article-title":"Antibody Validation by Western Blotting","volume":"1606","author":"Signore","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1002\/cpt.2745","article-title":"Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non-alcoholic Steatohepatitis","volume":"112","author":"Rabiee","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Ciofoaia, V., Chen, W., Tarek, B., Gay, M., Shivapurkar, N., and Smith, J. (2024). The Role of a Cholecystokinin Receptor Antagonist in the Management of Chronic Pancreatitis: A Phase 1 Trial. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16050611"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cell.2014.12.021","article-title":"Organoid models of human and mouse ductal pancreatic cancer","volume":"160","author":"Boj","year":"2015","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"G682","DOI":"10.1152\/ajpgi.00145.2019","article-title":"Vaccine against gastrin, a polyclonal antibody stimulator, decreases pancreatic cancer metastases","volume":"317","author":"Osborne","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1159\/000320540","article-title":"Pancreatic stellate cell models for transcriptional studies of desmoplasia-associated genes","volume":"10","author":"Mathison","year":"2010","journal-title":"Pancreatology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1186\/s12964-024-01742-3","article-title":"Signaling dynamics in coexisting monoclonal cell subpopulations unveil mechanisms of resistance to anti-cancer compounds","volume":"22","author":"Blanchard","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4919","DOI":"10.1158\/1078-0432.CCR-16-2656","article-title":"Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer","volume":"23","author":"Pierobon","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/978-1-4939-6990-6_11","article-title":"Reverse Phase Protein Microarrays","volume":"1606","author":"Baldelli","year":"2017","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11699\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T08:46:47Z","timestamp":1764751607000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,3]]},"references-count":80,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311699"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311699","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,3]]}}}