{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:03:01Z","timestamp":1790809381900,"version":"4.1.0"},"reference-count":166,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cancer Research UK for the Precision-Panc platform","award":["C51058\/A25407"],"award-info":[{"award-number":["C51058\/A25407"]}]},{"name":"Cancer Research UK for the Precision-Panc platform","award":["CTRQQR-2021\\100006"],"award-info":[{"award-number":["CTRQQR-2021\\100006"]}]},{"name":"Cancer Research UK for the Precision-Panc platform","award":["PCL\/22\/03"],"award-info":[{"award-number":["PCL\/22\/03"]}]},{"name":"Cancer Research UK Scotland Centre","award":["C51058\/A25407"],"award-info":[{"award-number":["C51058\/A25407"]}]},{"name":"Cancer Research UK Scotland Centre","award":["CTRQQR-2021\\100006"],"award-info":[{"award-number":["CTRQQR-2021\\100006"]}]},{"name":"Cancer Research UK Scotland Centre","award":["PCL\/22\/03"],"award-info":[{"award-number":["PCL\/22\/03"]}]},{"name":"Chief Scientist Office Postdoctoral Clinical Lectureship","award":["C51058\/A25407"],"award-info":[{"award-number":["C51058\/A25407"]}]},{"name":"Chief Scientist Office Postdoctoral Clinical Lectureship","award":["CTRQQR-2021\\100006"],"award-info":[{"award-number":["CTRQQR-2021\\100006"]}]},{"name":"Chief Scientist Office Postdoctoral Clinical Lectureship","award":["PCL\/22\/03"],"award-info":[{"award-number":["PCL\/22\/03"]}]},{"name":"McNab","award":["C51058\/A25407"],"award-info":[{"award-number":["C51058\/A25407"]}]},{"name":"McNab","award":["CTRQQR-2021\\100006"],"award-info":[{"award-number":["CTRQQR-2021\\100006"]}]},{"name":"McNab","award":["PCL\/22\/03"],"award-info":[{"award-number":["PCL\/22\/03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.<\/jats:p>","DOI":"10.3390\/cancers14215302","type":"journal-article","created":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T23:45:00Z","timestamp":1667087100000},"page":"5302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Adam S.","family":"Bryce","sequence":"first","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK"},{"name":"West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6134-2096","authenticated-orcid":false,"given":"Stephan B.","family":"Dreyer","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK"},{"name":"West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fieke E. M.","family":"Froeling","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK"},{"name":"Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK"},{"name":"Beatson West of Scotland Cancer Centre, 1053 Great Western Rd, Glasgow G12 0YN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4821-3078","authenticated-orcid":false,"given":"David K.","family":"Chang","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK"},{"name":"West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res."},{"key":"ref_2","unstructured":"World Health Organization (2021, March 30). International Agency for Research on Cancer\u2014GLOBOCAN 2020. Available online: https:\/\/gco.iarc.fr\/."},{"key":"ref_3","unstructured":"Cancer Research, U.K. (2022, April 04). Available online: https:\/\/www.cancerresearchuk.org\/health-professional\/cancer-statistics\/statistics-by-cancer-type\/pancreatic-cancer."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4266","DOI":"10.1158\/1078-0432.CCR-11-3114","article-title":"The Pancreas Cancer Microenvironment","volume":"18","author":"Feig","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1136\/gutjnl-2018-316451","article-title":"Stromal biology and therapy in pancreatic cancer: Ready for clinical translation?","volume":"68","author":"Neesse","year":"2019","journal-title":"Gut"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1146\/annurev.pathmechdis.3.121806.154305","article-title":"Pancreatic cancer","volume":"3","author":"Maitra","year":"2008","journal-title":"Annu. Rev. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1056\/NEJM198612253152606","article-title":"Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing","volume":"315","author":"Dvorak","year":"1986","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the crime: Functions of cells recruited to the tumor microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1158\/0008-5472.CAN-07-5714","article-title":"Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression","volume":"68","author":"Hwang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1126\/science.1195300","article-title":"Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein\u2013\u03b1","volume":"330","author":"Kraman","year":"2010","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1136\/gutjnl-2012-302529","article-title":"Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer","volume":"62","author":"Jacobetz","year":"2013","journal-title":"Gut"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.ccr.2014.04.005","article-title":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","volume":"25","author":"Carstens","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.ccr.2014.04.021","article-title":"Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma","volume":"25","author":"Rhim","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1158\/2159-8290.CD-19-0644","article-title":"Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy","volume":"10","author":"Dominguez","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41422-019-0195-y","article-title":"Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma","volume":"29","author":"Peng","year":"2019","journal-title":"Cell Res."},{"key":"ref_18","unstructured":"Virchow, R. (1858). Die Cellularpathologie in Ihrer Begrundung Auf Physiologische Und Pathologische Gewebelehre, August Hirschwald."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.biocel.2006.11.005","article-title":"Fibroblasts and myofibroblasts: Their source, function and role in disease","volume":"39","author":"McAnulty","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"C233","DOI":"10.1152\/ajpcell.00079.2020","article-title":"Recent advances in understanding cancer-associated fibroblasts in pancreatic cancer","volume":"319","author":"Huang","year":"2020","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1136\/gut.43.1.128","article-title":"Periacinar stellate shaped cells in rat pancreas: Identification, isolation, and culture","volume":"43","author":"Apte","year":"1998","journal-title":"Gut"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"636","DOI":"10.2353\/ajpath.2009.090131","article-title":"Organotypic Culture Model of Pancreatic Cancer Demonstrates that Stromal Cells Modulate E-Cadherin, \u03b2-Catenin, and Ezrin Expression in Tumor Cells","volume":"175","author":"Froeling","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Garcia, P.E., Scales, M.K., Allen, B.L., and Di Magliano, M.P. (2020). Pancreatic Fibroblast Heterogeneity: From Development to Cancer. Cells, 9.","DOI":"10.3390\/cells9112464"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s00262-017-2003-1","article-title":"Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy","volume":"66","author":"Jiang","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_28","first-page":"467","article-title":"Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage","volume":"1791","author":"Blaner","year":"2009","journal-title":"Biochim. et Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1053\/j.gastro.2011.06.047","article-title":"Retinoic Acid\u2013Induced Pancreatic Stellate Cell Quiescence Reduces Paracrine Wnt\u2013\u03b2-Catenin Signaling to Slow Tumor Progression","volume":"141","author":"Froeling","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fcell.2018.00131","article-title":"Macrophages and Fibroblasts, Key Players in Cancer Chemoresistance","volume":"6","author":"Ireland","year":"2018","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E1475","DOI":"10.1073\/pnas.1117988108","article-title":"Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition","volume":"108","author":"Rock","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1136\/gut.44.4.534","article-title":"Pancreatic stellate cells are activated by proinflammatory cytokines: Implications for pancreatic fibrogenesis","volume":"44","author":"Apte","year":"1999","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Geleta, B., Tout, F.S., Lim, S.C., Sahni, S., Jansson, P.J., Apte, M.V., Richardson, D.R., and Kova\u010devi\u0107, \u017d. (2022). Targeting Wnt\/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101608"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nature11547","article-title":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","volume":"491","author":"Biankin","year":"2012","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1053\/j.gastro.2011.12.042","article-title":"Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia","volume":"142","author":"Kanda","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1172\/JCI59227","article-title":"Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice","volume":"122","author":"Collins","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S1535-6108(03)00309-X","article-title":"Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse","volume":"4","author":"Hingorani","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.cell.2016.03.029","article-title":"Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation","volume":"165","author":"Tape","year":"2016","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.ccr.2010.04.018","article-title":"Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-\u03baB-dependent manner","volume":"17","author":"Erez","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.cell.2018.01.009","article-title":"CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness","volume":"172","author":"Su","year":"2018","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.arr.2007.09.002","article-title":"Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging","volume":"7","author":"Salminen","year":"2008","journal-title":"Ageing Res. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1593\/neo.11332","article-title":"Interleukin 1\u03b1 sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts","volume":"13","author":"Tjomsland","year":"2011","journal-title":"Neoplasia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"81110","DOI":"10.18632\/oncotarget.13212","article-title":"Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma","volume":"7","author":"Zhao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1158\/0008-5472.CAN-17-1366","article-title":"Tumor-stroma IL1\u03b2-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer","volume":"78","author":"Zhang","year":"2018","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5020","DOI":"10.1158\/0008-5472.CAN-11-0908","article-title":"STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis","volume":"71","author":"Corcoran","year":"2011","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.ccr.2011.03.009","article-title":"Stat3\/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer","volume":"19","author":"Lesina","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10204","DOI":"10.1038\/ncomms10204","article-title":"Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts","volume":"6","author":"Albrengues","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nrm809","article-title":"Myofibroblasts and mechano-regulation of connective tissue remodelling","volume":"3","author":"Tomasek","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0002-9440(10)62991-4","article-title":"Stroma-Derived Three-Dimensional Matrices Are Necessary and Sufficient to Promote Desmoplastic Differentiation of Normal Fibroblasts","volume":"167","author":"Amatangelo","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.matbio.2018.11.001","article-title":"Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer cell spread via extracellular signal-regulated kinase 2","volume":"81","author":"Malik","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.cell.2014.05.045","article-title":"The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy","volume":"158","author":"Santagata","year":"2014","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-07987-0","article-title":"Dickkopf-3 links HSF1 and YAP\/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts","volume":"10","author":"Ferrari","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1053\/j.gastro.2010.05.084","article-title":"CD10+ Pancreatic Stellate Cells Enhance the Progression of Pancreatic Cancer","volume":"139","author":"Ikenaga","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.cels.2016.08.011","article-title":"A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure","volume":"3","author":"Baron","year":"2016","journal-title":"Cell Syst."},{"key":"ref_56","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":"Ohlund","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41421-021-00271-4","article-title":"Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response","volume":"7","author":"Wang","year":"2021","journal-title":"Cell Discov."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Hosein, A.N., Huang, H., Wang, Z., Parmar, K., Du, W., Huang, J., Maitra, A., Olson, E., Verma, U., and Brekken, R.A. (2019). Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight, 4.","DOI":"10.1172\/jci.insight.129212"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1158\/1078-0432.CCR-18-1955","article-title":"Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression","volume":"25","author":"Bernard","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/j.ccell.2021.06.017","article-title":"Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity","volume":"39","author":"Hutton","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/path.5224","article-title":"Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma","volume":"248","author":"Neuzillet","year":"2018","journal-title":"J. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"E1147","DOI":"10.1073\/pnas.1717802115","article-title":"Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors","volume":"115","author":"Djurec","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"103315","DOI":"10.1016\/j.ebiom.2021.103315","article-title":"Single-cell RNA-seq reveals dynamic change in tumor microenvironment during pancreatic ductal adenocarcinoma malignant progression","volume":"66","author":"Chen","year":"2021","journal-title":"eBioMedicine"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s00595-017-1559-x","article-title":"Expression of podoplanin in stromal fibroblasts plays a pivotal role in the prognosis of patients with pancreatic cancer","volume":"48","author":"Hirayama","year":"2018","journal-title":"Surg. Today"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1083\/jcb.130.2.393","article-title":"Identification and characterization of a fibroblast marker: FSP1","volume":"130","author":"Strutz","year":"1995","journal-title":"J. Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/s43018-020-0082-y","article-title":"Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome","volume":"1","author":"Friedman","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ccell.2018.01.011","article-title":"Fibroblast heterogeneity and immunosuppressive environment in human breast cancer","volume":"33","author":"Costa","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.ccell.2021.02.007","article-title":"Type I collagen deletion in \u03b1SMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer","volume":"39","author":"Chen","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_69","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_70","doi-asserted-by":"crossref","first-page":"e9085","DOI":"10.15252\/emmm.201809085","article-title":"Dual reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program","volume":"10","author":"Chen","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1097\/SLA.0000000000003143","article-title":"Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer","volume":"272","author":"Dreyer","year":"2020","journal-title":"Ann. Surg."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1158\/2159-8290.CD-18-0710","article-title":"IL1-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_73","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/s41571-021-00546-5","article-title":"Clinical and therapeutic relevance of cancer-associated fibroblasts","volume":"18","author":"Chen","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_74","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_75","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41586-019-1130-6","article-title":"Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring","volume":"569","author":"Shi","year":"2019","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"20212","DOI":"10.1073\/pnas.1320318110","article-title":"Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer","volume":"110","author":"Feig","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1158\/0008-5472.CAN-12-4601","article-title":"Pancreatic Cancer-Associated Stellate Cells Promote Differentiation of Myeloid-Derived Suppressor Cells in a STAT3-Dependent Manner","volume":"73","author":"Mace","year":"2013","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1158\/0008-5472.CAN-15-1293","article-title":"TGF\u03b2 signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis","volume":"76","author":"Principe","year":"2016","journal-title":"Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ccr.2005.10.012","article-title":"TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance","volume":"8","author":"Thomas","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of tumor-associated neutrophil phenotype by TGF-beta: \u201cN1\u201d versus \u201cN2\u201d, TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGF\u03b2 attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-10968-6","article-title":"CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan","volume":"10","author":"Vennin","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"101417","DOI":"10.1016\/j.smim.2020.101417","article-title":"Fibroblast heterogeneity in tumor micro-environment: Role in immunosuppression and new therapies","volume":"48","author":"Mhaidly","year":"2020","journal-title":"Semin. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nm.4123","article-title":"Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy","volume":"22","author":"Jiang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.1158\/1078-0432.CCR-13-2972","article-title":"Prevailing Role of Contact Guidance in Intrastromal T-cell Trapping in Human Pancreatic Cancer","volume":"20","author":"Hartmann","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.ccr.2012.01.007","article-title":"Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma","volume":"21","author":"Provenzano","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1200\/JCO.2017.74.9564","article-title":"HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel\/Gemcitabine Versus Nab-Paclitaxel\/Gemcitabine in Patients with Untreated, Metastatic Pancreatic Ductal Adenocarcinoma","volume":"36","author":"Hingorani","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1200\/JCO.2020.38.4_suppl.638","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":"Tempero","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1158\/0008-5472.CAN-14-2211","article-title":"Human Pancreatic Cancer Tumors Are Nutrient Poor and Tumor Cells Actively Scavenge Extracellular Protein","volume":"75","author":"Kamphorst","year":"2015","journal-title":"Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1158\/2159-8290.CD-21-0601","article-title":"Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer\u2013Associated Fibroblasts","volume":"12","author":"Helms","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nature19084","article-title":"Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion","volume":"536","author":"Sousa","year":"2016","journal-title":"Nature"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"16031","DOI":"10.1038\/ncomms16031","article-title":"Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions","volume":"8","author":"Olivares","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"8882","DOI":"10.1073\/pnas.1307237110","article-title":"Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids","volume":"110","author":"Kamphorst","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1158\/2159-8290.CD-18-1212","article-title":"A Stromal Lysolipid\u2013Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression","volume":"9","author":"Auciello","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1158\/2159-8290.CD-19-0959","article-title":"Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer","volume":"10","author":"Parker","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5723","DOI":"10.1158\/0008-5472.CAN-19-0960","article-title":"Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance","volume":"79","author":"Dalin","year":"2019","journal-title":"Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e10250","DOI":"10.7554\/eLife.10250","article-title":"Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism","volume":"5","author":"Zhao","year":"2016","journal-title":"eLife"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1038\/onc.2016.353","article-title":"Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells","volume":"36","author":"Richards","year":"2017","journal-title":"Oncogene"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1158\/2159-8290.CD-19-1353","article-title":"Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment","volume":"10","author":"Helms","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"E3091","DOI":"10.1073\/pnas.1411679111","article-title":"Stromal response to Hedgehog signaling restrains pancreatic cancer progression","volume":"111","author":"Lee","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1158\/1078-0432.CCR-20-3715","article-title":"Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer","volume":"27","author":"Steele","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"5937","DOI":"10.1158\/1078-0432.CCR-14-1269","article-title":"Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma","volume":"20","author":"Kim","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1097\/MPA.0000000000000458","article-title":"A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma","volume":"45","author":"Ko","year":"2016","journal-title":"Pancreas"},{"key":"ref_104","first-page":"498","article-title":"Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma","volume":"122","author":"Sugar","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_105","unstructured":"(2022, August 04). Olive Lab, IPI-926-03. Available online: https:\/\/www.olivelab.org\/ipi-926-03.html."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.17.00121","article-title":"Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma","volume":"2","author":"Torphy","year":"2018","journal-title":"JCO Precis. Oncol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s10637-018-0580-2","article-title":"Ruxolitinib + capecitabine in advanced\/metastatic pancreatic cancer after disease progression\/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies","volume":"36","author":"Hurwitz","year":"2018","journal-title":"Investig. New Drugs"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4039","DOI":"10.1200\/JCO.2015.61.4578","article-title":"Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed","volume":"33","author":"Hurwitz","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_109","unstructured":"Bell, A.T., Mitchell, J.T., Kiemen, A.L., Fujikura, K., Fedor, H., Gambichler, B., Deshpande, A., Wu, P.H., Sidiropoulos, D.N., and Erbe, R. (2022). Spatial transcriptomics of FFPE pancreatic intraepithelial neoplasias reveals cellular and molecular alterations of progression to pancreatic ductal carcinoma. bioRxiv."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12864-018-4772-0","article-title":"Slingshot: Cell lineage and pseudotime inference for single-cell transcriptomics","volume":"19","author":"Street","year":"2018","journal-title":"BMC Genom."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1158\/1538-7445.AM2022-3647","article-title":"Abstract 3647: Oncogenic Kras drives cancer-associated fibroblast heterogeneity and substate changes in pancreatic cancer","volume":"82","author":"Thalappillil","year":"2022","journal-title":"Cancer Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1158\/1538-7445.AM2022-1563","article-title":"Abstract 1563: Spatial transcriptomics reveals heterogeneity and pathway dependencies of cancer associated fibroblasts in pancreatic ductal adenocarcinoma","volume":"82","author":"Caligiuri","year":"2022","journal-title":"Cancer Res."},{"key":"ref_113","first-page":"940","article-title":"A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression","volume":"24","author":"Verginadis","year":"2022","journal-title":"Nature"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"104659","DOI":"10.1016\/j.isci.2022.104659","article-title":"Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma","volume":"25","author":"Chijimatsu","year":"2022","journal-title":"iScience"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1136\/gutjnl-2020-322744","article-title":"Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism","volume":"71","author":"Sun","year":"2021","journal-title":"Gut"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-021-27607-8","article-title":"Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis","volume":"12","author":"Lee","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1053\/j.gastro.2022.02.024","article-title":"Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment","volume":"162","author":"Garcia","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"5577","DOI":"10.1016\/j.cell.2021.09.022","article-title":"Spatially confined sub-tumor microenvironments in pancreatic cancer","volume":"184","author":"Devisme","year":"2021","journal-title":"Cell"},{"key":"ref_120","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_121","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_122","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nm.2344","article-title":"Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy","volume":"17","author":"Collisson","year":"2011","journal-title":"Nat. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1053\/j.gastro.2021.09.022","article-title":"Genomic and Molecular Analyses Identify Molecular Subtypes of Pancreatic Cancer Recurrence","volume":"162","author":"Dreyer","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2018.08.033","article-title":"Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features","volume":"155","author":"Puleo","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_125","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_126","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40425-018-0316-z","article-title":"Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations","volume":"6","author":"Gong","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1001\/jamaoncol.2019.1588","article-title":"Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: A phase 2 randomized clinical trial","volume":"5","author":"Oh","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1053\/j.gastro.2018.12.038","article-title":"Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities","volume":"156","author":"Balachandran","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ccell.2020.02.010","article-title":"Context-dependent immune responses explain pancreatic cancer immunoresistance","volume":"37","author":"Bednar","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"4814","DOI":"10.1158\/1078-0432.CCR-20-0099","article-title":"Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer","volume":"26","author":"Wainberg","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12943-020-01151-3","article-title":"Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma","volume":"19","author":"Fan","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1158\/1535-7163.MCT-18-0850","article-title":"TGF\u03b2 Blockade Augments PD-1 Inhibition to Promote T-Cell\u2013Mediated Regression of Pancreatic Cancer","volume":"18","author":"Principe","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1158\/2159-8290.CD-19-0958","article-title":"Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis","volume":"10","author":"Zhang","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.ccell.2016.04.014","article-title":"CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma","volume":"29","author":"Steele","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.celrep.2018.03.131","article-title":"CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype","volume":"23","author":"Candido","year":"2018","journal-title":"Cell Rep."},{"key":"ref_136","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 IL6-Mediated Therapy Resistance in Pancreatic Cancer","volume":"12","author":"McAndrews","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1200\/JCO.21.02233","article-title":"Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial","volume":"40","author":"Versteijne","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1053\/j.gastro.2015.02.043","article-title":"Homeostatic Restoration of Desmoplastic Stroma Rather Than Its Ablation Slows Pancreatic Cancer Progression","volume":"148","author":"Froeling","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-18636-w","article-title":"Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer","volume":"11","author":"Kocher","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1053\/j.gastro.2013.07.025","article-title":"Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma","volume":"145","author":"Clear","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/path.4727","article-title":"Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma","volume":"239","author":"Gemenetzidis","year":"2016","journal-title":"J. Pathol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1016\/j.pan.2020.10.009","article-title":"STARPAC clinical trial","volume":"20","author":"Kocher","year":"2020","journal-title":"Pancreatology"},{"key":"ref_143","unstructured":"(2022, September 03). Precision-Panc. Available online: www.precisionpanc.org."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.cell.2014.08.007","article-title":"Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy","volume":"159","author":"Sherman","year":"2014","journal-title":"Cell"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"17444","DOI":"10.1038\/s41598-020-74368-3","article-title":"The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity","volume":"10","author":"Gorchs","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.cmet.2016.10.010","article-title":"Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity","volume":"24","author":"Flint","year":"2016","journal-title":"Cell Metab."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1136\/gutjnl-2016-311585","article-title":"IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer","volume":"67","author":"Mace","year":"2016","journal-title":"Gut"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1158\/1078-0432.CCR-14-3382","article-title":"IL1 receptor antagonist inhibits pancreatic cancer growth by abrogating NF-\u03baB activation","volume":"22","author":"Zhuang","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1053\/j.gastro.2018.05.051","article-title":"NF\u03baB in pancreatic stellate cells reduces infiltration of tumors by cytotoxic T cells and killing of cancer cells, via up-regulation of CXCL12","volume":"155","author":"Garg","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/nature07275","article-title":"A paracrine requirement for hedgehog signalling in cancer","volume":"455","author":"Yauch","year":"2008","journal-title":"Nature"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1073\/pnas.1018892108","article-title":"Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors","volume":"108","author":"Chauhan","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1038\/ncomms3516","article-title":"Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels","volume":"4","author":"Chauhan","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1007\/s00280-019-03807-4","article-title":"TGF\u03b2 receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer","volume":"83","author":"Melisi","year":"2019","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s00280-017-3313-x","article-title":"Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer","volume":"79","author":"Ikeda","year":"2017","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"e002068","DOI":"10.1136\/jitc-2020-002068","article-title":"Safety and activity of the TGF\u03b2 receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer","volume":"9","author":"Melisi","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1200\/JCO.2021.39.15_suppl.2503","article-title":"Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-\u03b2, in patients with advanced solid tumors","volume":"39","author":"Liu","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1200\/JCO.2022.40.4_suppl.568","article-title":"Phase II study of SHR-1701 combined with famitinib in the treatment of advanced pancreatic cancer or biliary tract cancer","volume":"40","author":"Xie","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.1158\/0008-5472.CAN-19-0454","article-title":"Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis","volume":"79","author":"Mizutani","year":"2019","journal-title":"Cancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-022-09272-2","article-title":"Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: A study protocol for an open-label phase I\/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma","volume":"22","author":"Mizutani","year":"2022","journal-title":"BMC Cancer"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1111\/cas.14346","article-title":"Cancer-associated fibroblasts that restrain cancer progression: Hypotheses and perspectives","volume":"111","author":"Miyai","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"e10515","DOI":"10.15252\/emmm.201910515","article-title":"Targeting TGF \u03b2R2-mutant tumors exposes vulnerabilities to stromal TGF \u03b2 blockade in pancreatic cancer","volume":"11","author":"Huang","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"15095","DOI":"10.1038\/ncomms15095","article-title":"Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer","volume":"8","author":"Carstens","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Ando, R., Sakai, A., Iida, T., Kataoka, K., Mizutani, Y., and Enomoto, A. (2022). Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts. Cancers, 14.","DOI":"10.3390\/cancers14143315"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"655152","DOI":"10.3389\/fcell.2021.655152","article-title":"Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer","volume":"9","author":"Geng","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2016.03.014","article-title":"On the Dependency of Cellular Protein Levels on mRNA Abundance","volume":"165","author":"Liu","year":"2016","journal-title":"Cell"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Moffitt, J.R., Lundberg, E., and Heyn, H. (2022). The emerging landscape of spatial profiling technologies. Nat. Rev. Genet., 1\u201319.","DOI":"10.1038\/s41576-022-00515-3"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/21\/5302\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:04:50Z","timestamp":1760144690000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/21\/5302"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,28]]},"references-count":166,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["cancers14215302"],"URL":"https:\/\/doi.org\/10.3390\/cancers14215302","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,28]]}}}