{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:59:49Z","timestamp":1791496789213,"version":"4.3.4"},"reference-count":142,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002661","name":"FNRS","doi-asserted-by":"publisher","award":["40000551"],"award-info":[{"award-number":["40000551"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondation L\u00e9on Fredericq","award":["40000551"],"award-info":[{"award-number":["40000551"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF\/cancer cell crosstalk could pave the way for new therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cancers15010061","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:26:25Z","timestamp":1671765985000},"page":"61","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer"],"prefix":"10.3390","volume":"15","author":[{"given":"Rapha\u00ebl","family":"Peiffer","sequence":"first","affiliation":[{"name":"Metastasis Research Laboratory, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Boumahd","sequence":"additional","affiliation":[{"name":"Metastasis Research Laboratory, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Gullo","sequence":"additional","affiliation":[{"name":"Metastasis Research Laboratory, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekah","family":"Crake","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8242-9393","authenticated-orcid":false,"given":"Elisabeth","family":"Letellier","sequence":"additional","affiliation":[{"name":"Molecular Disease Mechanisms Group, University of Luxembourg, Campus Belval, 4367 Esch-sur-Alzette, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9154-7631","authenticated-orcid":false,"given":"Akeila","family":"Bellahc\u00e8ne","sequence":"additional","affiliation":[{"name":"Metastasis Research Laboratory, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6933-0134","authenticated-orcid":false,"given":"Olivier","family":"Peulen","sequence":"additional","affiliation":[{"name":"Metastasis Research Laboratory, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s13014-019-1345-6","article-title":"Pancreatic Ductal Adenocarcinoma: Biological Hallmarks, Current Status, and Future Perspectives of Combined Modality Treatment Approaches","volume":"14","author":"Orth","year":"2019","journal-title":"Radiat. Oncol."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/PPO.0000000000000288","article-title":"The Pancreatic Cancer Microenvironment","volume":"23","author":"Dougan","year":"2017","journal-title":"Cancer J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Belhabib, I., Zaghdoudi, S., Lac, C., Bousquet, C., and Jean, C. (2021). Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?. Cancers, 13.","DOI":"10.3390\/cancers13143466"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"882","DOI":"10.4161\/cbt.7.6.5869","article-title":"Pancreatic Cancer Associated Fibroblasts Display Normal Allelotypes","volume":"7","author":"Walter","year":"2008","journal-title":"Cancer Biol. Ther."},{"key":"ref_6","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_7","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_8","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1053\/j.gastro.2004.12.036","article-title":"Pancreatic Carcinoma Cells Induce Fibrosis by Stimulating Proliferation and Matrix Synthesis of Stellate Cells","volume":"128","author":"Bachem","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_9","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":"2022","journal-title":"Cancer Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7551","DOI":"10.1073\/pnas.1600363113","article-title":"Tumor-Associated Fibroblasts Predominantly Come from Local and Not Circulating Precursors","volume":"113","author":"Arina","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4690","DOI":"10.1038\/s41598-021-84058-3","article-title":"Adipose-Derived Mesenchymal Stem Cells Differentiate into Heterogeneous Cancer-Associated Fibroblasts in a Stroma-Rich Xenograft Model","volume":"11","author":"Miyazaki","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.jcmgh.2020.05.004","article-title":"Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma","volume":"10","author":"Garcia","year":"2020","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1593\/neo.11088","article-title":"Ectopic Overexpression of Sonic Hedgehog (Shh) Induces Stromal Expansion and Metaplasia in the Adult Murine Pancreas","volume":"13","author":"Fendrich","year":"2011","journal-title":"Neoplasia"},{"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":"36","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_17","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.ajpath.2015.01.016","article-title":"Patient-Derived Xenograft Models for Pancreatic Adenocarcinoma Demonstrate Retention of Tumor Morphology through Incorporation of Murine Stromal Elements","volume":"185","author":"Delitto","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1083\/jcb.122.1.103","article-title":"Transforming Growth Factor-Beta 1 Induces Alpha-Smooth Muscle Actin Expression in Granulation Tissue Myofibroblasts and in Quiescent and Growing Cultured Fibroblasts","volume":"122","author":"Geinoz","year":"1993","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/sj.jid.5700613","article-title":"Formation and Function of the Myofibroblast during Tissue Repair","volume":"127","author":"Hinz","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ejphar.2014.04.007","article-title":"Reversal of Myofibroblast Differentiation: A Review","volume":"734","author":"Yang","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and Molecular Mechanisms of Fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1002\/art.21948","article-title":"Association between Enhanced Type I Collagen Expression and Epigenetic Repression of the FLI1 Gene in Scleroderma Fibroblasts","volume":"54","author":"Wang","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_24","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_25","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_26","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1002\/ijc.32193","article-title":"In Search of Definitions: Cancer-Associated Fibroblasts and Their Markers","volume":"146","author":"Nurmik","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.molonc.2014.04.006","article-title":"Differences between CAFs and Their Paired NCF from Adjacent Colonic Mucosa Reveal Functional Heterogeneity of CAFs, Providing Prognostic Information","volume":"8","author":"Calon","year":"2014","journal-title":"Mol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1084\/jem.20162024","article-title":"Distinct Populations of Inflammatory Fibroblasts and Myofibroblasts in Pancreatic Cancer","volume":"214","author":"Biffi","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e129212","DOI":"10.1172\/jci.insight.129212","article-title":"Cellular Heterogeneity during Mouse Pancreatic Ductal Adenocarcinoma Progression at Single-Cell Resolution","volume":"4","author":"Hosein","year":"2019","journal-title":"JCI Insight"},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41586-022-05272-1","article-title":"LRRC15+ Myofibroblasts Dictate the Stromal Setpoint to Suppress Tumour Immunity","volume":"611","author":"Krishnamurty","year":"2022","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1476-4598-3-26","article-title":"Molecular Regulation of Pancreatic Stellate Cell Function","volume":"3","author":"Jaster","year":"2004","journal-title":"Mol. Cancer"},{"key":"ref_34","first-page":"6526","article-title":"The Role of Transforming Growth Factor Beta 1 in the Fibroblastic Reaction Associated with Rat Colorectal Tumor Development","volume":"54","author":"Lieubeau","year":"1994","journal-title":"Cancer Res."},{"key":"ref_35","first-page":"550","article-title":"Transforming Growth Factor-Beta1 Induces Desmoplasia in an Experimental Model of Human Pancreatic Carcinoma","volume":"61","author":"Schmidt","year":"2001","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nrc3603","article-title":"The Roles of TGF\u03b2 in the Tumour Microenvironment","volume":"13","author":"Pickup","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00432-X","article-title":"Mechanisms of TGF-\u03b2 Signaling from Cell Membrane to the Nucleus","volume":"113","author":"Shi","year":"2003","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1093\/emboj\/17.11.3091","article-title":"Direct Binding of Smad3 and Smad4 to Critical TGF\u03b2-Inducible Elements in the Promoter of Human Plasminogen Activator Inhibitor-Type 1 Gene","volume":"17","author":"Dennler","year":"1998","journal-title":"EMBO J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1016\/j.febslet.2006.04.033","article-title":"The Logic of TGF\u03b2 Signaling","volume":"580","author":"Gomis","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1002\/jcp.25049","article-title":"Tamoxifen Inhibits TGF-\u03b2-Mediated Activation of Myofibroblasts by Blocking Non-Smad Signaling Through ERK1\/2","volume":"230","author":"Carthy","year":"2015","journal-title":"J. Cell Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nature02009","article-title":"Hedgehog Is an Early and Late Mediator of Pancreatic Cancer Tumorigenesis","volume":"425","author":"Thayer","year":"2003","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1101\/gad.938601","article-title":"Hedgehog Signaling in Animal Development: Paradigms and Principles","volume":"15","author":"Ingham","year":"2001","journal-title":"Genes Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4254","DOI":"10.1073\/pnas.0813203106","article-title":"Hedgehog Signaling Is Restricted to the Stromal Compartment during Pancreatic Carcinogenesis","volume":"106","author":"Tian","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1158\/1078-0432.CCR-08-0291","article-title":"Sonic Hedgehog Promotes Desmoplasia in Pancreatic Cancer","volume":"14","author":"Bailey","year":"2008","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_45","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. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_46","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":"2019","journal-title":"Matrix Biol."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"e53381","DOI":"10.7554\/eLife.53381","article-title":"Squamous Trans-Differentiation of Pancreatic Cancer Cells Promotes Stromal Inflammation","volume":"9","author":"Somerville","year":"2020","journal-title":"eLife"},{"key":"ref_49","first-page":"2902","article-title":"Murine B16 Melanomas Expressing High Levels of the Chemokine Stromal-Derived Factor-1\/CXCL12 Induce Tumor-Specific T Cell Chemorepulsion and Escape from Immune Control","volume":"176","author":"Vianello","year":"2006","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/75022","article-title":"Active Movement of T Cells Away from a Chemokine","volume":"6","author":"Poznansky","year":"2000","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.2174\/0929867324666170830111531","article-title":"Targeting CXCL12\/CXCR4 Axis in Tumor Immunotherapy","volume":"26","author":"Zhou","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.canlet.2012.02.035","article-title":"SDF-1\/CXCR4 Signaling Induces Pancreatic Cancer Cell Invasion and Epithelial-Mesenchymal Transition in Vitro through Non-Canonical Activation of Hedgehog Pathway","volume":"322","author":"Li","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13046-016-0301-7","article-title":"Transcriptional Repression of SOCS3 Mediated by IL-6\/STAT3 Signaling via DNMT1 Promotes Pancreatic Cancer Growth and Metastasis","volume":"35","author":"Huang","year":"2016","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.bbagen.2016.10.006","article-title":"Paracrine IL-6 Signaling Mediates the Effects of Pancreatic Stellate Cells on Epithelial-Mesenchymal Transition via Stat3\/Nrf2 Pathway in Pancreatic Cancer Cells","volume":"1861","author":"Wu","year":"2017","journal-title":"Biochim. Biophys. Acta BBA\u2014Gen. Subj."},{"key":"ref_55","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_56","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_57","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1146\/annurev.immunol.15.1.797","article-title":"Gp130 and the Interleukin-6 Family of Cytokines","volume":"15","author":"Taga","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1084\/jem.172.3.737","article-title":"Transforming Growth Factor Beta Is a Potent Inhibitor of Interleukin 1 (IL-1) Receptor Expression: Proposed Mechanism of Inhibition of IL-1 Action","volume":"172","author":"Dubois","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_59","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_60","doi-asserted-by":"crossref","first-page":"664-IN3","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_61","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1158\/0008-5472.CAN-19-2080","article-title":"Tumor Cell\u2013Derived IL1\u03b2 Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer","volume":"80","author":"Das","year":"2020","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"22288","DOI":"10.1038\/srep22288","article-title":"Identification of Meflin as a Potential Marker for Mesenchymal Stromal Cells","volume":"6","author":"Maeda","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_63","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_64","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_65","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_66","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_67","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1158\/1078-0432.CCR-20-1039","article-title":"Transcriptomic Analysis of Laser Capture Microdissected Tumors Reveals Cancer- and Stromal-Specific Molecular Subtypes of Pancreatic Ductal Adenocarcinoma","volume":"27","author":"Birnbaum","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41568-021-00378-6","article-title":"Cancer Metabolism: Looking Forward","volume":"21","author":"Chandel","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/BF01504608","article-title":"\u00dcber Den Stoffwechsel Der Carcinomzelle","volume":"12","author":"Warburg","year":"1924","journal-title":"Naturwissenschaften"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s42255-020-0172-2","article-title":"We Need to Talk about the Warburg Effect","volume":"2","author":"DeBerardinis","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/nature13611","article-title":"Oncogene Ablation-Resistant Pancreatic Cancer Cells Depend on Mitochondrial Function","volume":"514","author":"Viale","year":"2014","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4398","DOI":"10.1038\/s41388-018-0287-z","article-title":"Myoferlin Controls Mitochondrial Structure and Activity in Pancreatic Ductal Adenocarcinoma, and Affects Tumor Aggressiveness","volume":"37","author":"Rademaker","year":"2018","journal-title":"Oncogene"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41586-020-2475-6","article-title":"Mitochondrial Ubiquinol Oxidation Is Necessary for Tumor Growth","volume":"585","author":"Kong","year":"2020","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2007.10.002","article-title":"The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation","volume":"7","author":"DeBerardinis","year":"2008","journal-title":"Cell Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1158\/2159-8290.CD-15-0671","article-title":"Pancreatic Cancer Metabolism: Breaking It Down to Build It Back Up","volume":"5","author":"Perera","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1093\/carcin\/bgu097","article-title":"The Complex Landscape of Pancreatic Cancer Metabolism","volume":"35","author":"Sousa","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6658","DOI":"10.1073\/pnas.94.13.6658","article-title":"C-Myc Transactivation of LDH-A: Implications for Tumor Metabolism and Growth","volume":"94","author":"Shim","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.cell.2012.01.058","article-title":"Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism","volume":"149","author":"Ying","year":"2012","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"78396","DOI":"10.18632\/oncotarget.11893","article-title":"Unique Metabolic Features of Pancreatic Cancer Stroma: Relevance to the Tumor Compartment, Prognosis, and Invasive Potential","volume":"7","author":"Knudsen","year":"2016","journal-title":"Oncotarget"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.celrep.2015.02.006","article-title":"Metabolic Reprogramming of Cancer-Associated Fibroblasts by IDH3\u03b1 Downregulation","volume":"10","author":"Zhang","year":"2015","journal-title":"Cell Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.4161\/cc.8.23.10238","article-title":"The Reverse Warburg Effect: Aerobic Glycolysis in Cancer Associated Fibroblasts and the Tumor Stroma","volume":"8","author":"Pavlides","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_83","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_84","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nature10642","article-title":"Reductive Carboxylation Supports Growth in Tumour Cells with Defective Mitochondria","volume":"481","author":"Mullen","year":"2012","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"19611","DOI":"10.1073\/pnas.1117773108","article-title":"Hypoxia Promotes Isocitrate Dehydrogenase-Dependent Carboxylation of \u03b1-Ketoglutarate to Citrate to Support Cell Growth and Viability","volume":"108","author":"Wise","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature10602","article-title":"Reductive Glutamine Metabolism by IDH1 Mediates Lipogenesis under Hypoxia","volume":"481","author":"Metallo","year":"2012","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nature12138","article-title":"Macropinocytosis of Protein Is an Amino Acid Supply Route in Ras-Transformed Cells","volume":"497","author":"Commisso","year":"2013","journal-title":"Nature"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/s42255-020-0226-5","article-title":"Tumour-Reprogrammed Stromal BCAT1 Fuels Branched-Chain Ketoacid Dependency in Stromal-Rich PDAC Tumours","volume":"2","author":"Zhu","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_89","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_90","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_91","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/0092-8674(88)90571-5","article-title":"Most Human Carcinomas of the Exocrine Pancreas Contain Mutant C-K-Ras Genes","volume":"53","author":"Almoguera","year":"1988","journal-title":"Cell"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1073\/pnas.1620164114","article-title":"Stromal Cues Regulate the Pancreatic Cancer Epigenome and Metabolome","volume":"114","author":"Sherman","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.yexcr.2018.07.041","article-title":"Paracrine HGF\/c-MET Enhances the Stem Cell-like Potential and Glycolysis of Pancreatic Cancer Cells via Activation of YAP\/HIF-1\u03b1","volume":"371","author":"Yan","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_94","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_95","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1038\/s41467-020-15104-3","article-title":"Cancer Associated Fibroblast FAK Regulates Malignant Cell Metabolism","volume":"11","author":"Demircioglu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"M111.014647","DOI":"10.1074\/mcp.M111.014647","article-title":"The Matrisome: In Silico Definition and In Vivo Characterization by Proteomics of Normal and Tumor Extracellular Matrices","volume":"11","author":"Naba","year":"2012","journal-title":"Mol. Cell Proteom. MCP"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"19609","DOI":"10.1073\/pnas.1908626116","article-title":"Proteomic Analyses of ECM during Pancreatic Ductal Adenocarcinoma Progression Reveal Different Contributions by Tumor and Stromal Cells","volume":"116","author":"Tian","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/nrc1456","article-title":"High Interstitial Fluid Pressure\u2014An Obstacle in Cancer Therapy","volume":"4","author":"Heldin","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0360-3016(00)00803-8","article-title":"Pancreatic Tumors Show High Levels of Hypoxia","volume":"48","author":"Koong","year":"2000","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1038\/s41467-020-18794-x","article-title":"Concepts of Extracellular Matrix Remodelling in Tumour Progression and Metastasis","volume":"11","author":"Winkler","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1148\/86.3.470","article-title":"Arteriographic Diagnosis of Pancreatic Lesions","volume":"86","author":"Ranniger","year":"1966","journal-title":"Radiology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"288","DOI":"10.2174\/156652412799218921","article-title":"The Impact of the Activated Stroma on Pancreatic Ductal Adenocarcinoma Biology and Therapy Resistance","volume":"12","author":"Erkan","year":"2012","journal-title":"Curr. Mol. Med."},{"key":"ref_103","first-page":"7298","article-title":"Generation of Multiple Angiogenesis Inhibitors by Human Pancreatic Cancer1","volume":"61","author":"Kisker","year":"2001","journal-title":"Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"G709","DOI":"10.1152\/ajpgi.90356.2008","article-title":"Hypoxia Stimulates Pancreatic Stellate Cells to Induce Fibrosis and Angiogenesis in Pancreatic Cancer","volume":"295","author":"Masamune","year":"2008","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1593\/neo.81618","article-title":"Cancer-Stellate Cell Interactions Perpetuate the Hypoxia-Fibrosis Cycle in Pancreatic Ductal Adenocarcinoma","volume":"11","author":"Erkan","year":"2009","journal-title":"Neoplasia"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1158\/0008-5472.CAN-11-1433","article-title":"Hypoxia Triggers Hedgehog-Mediated Tumor-Stromal Interactions in Pancreatic Cancer","volume":"73","author":"Hostetter","year":"2013","journal-title":"Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"6529","DOI":"10.1158\/1078-0432.CCR-14-0970","article-title":"Extracellular Lumican Inhibits Pancreatic Cancer Cell Growth and Is Associated with Prolonged Survival after Surgery","volume":"20","author":"Li","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41418-018-0207-3","article-title":"Hypoxia-Induced Autophagy of Stellate Cells Inhibits Expression and Secretion of Lumican into Microenvironment of Pancreatic Ductal Adenocarcinoma","volume":"26","author":"Li","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1158\/0008-5472.CAN-10-4049","article-title":"Hypoxia Predicts Aggressive Growth and Spontaneous Metastasis Formation from Orthotopically Grown Primary Xenografts of Human Pancreatic Cancer","volume":"71","author":"Chang","year":"2011","journal-title":"Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40169-019-0226-9","article-title":"Hypoxia as a Barrier to Immunotherapy in Pancreatic Adenocarcinoma","volume":"8","author":"Daniel","year":"2019","journal-title":"Clin. Transl. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.molcel.2008.04.009","article-title":"Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway","volume":"30","author":"Kaelin","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_112","first-page":"391","article-title":"Hypoxia-Inducible Factor 1\u03b1 Expression and Its Clinical Significance in Pancreatic Cancer: A Meta-Analysis","volume":"14","author":"Ye","year":"2014","journal-title":"Pancreatol. Off. J. Int. Assoc. Pancreatol. IAP Al"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1586\/17474124.2016.1117386","article-title":"The Role of Hypoxia in Pancreatic Cancer: A Potential Therapeutic Target?","volume":"10","author":"Erkan","year":"2016","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"25130","DOI":"10.1074\/jbc.M001914200","article-title":"Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-Inducible Factor-1alpha during Hypoxia: A Mechanism of O2 Sensing","volume":"275","author":"Chandel","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1073\/pnas.1219555110","article-title":"Strengthened Glycolysis under Hypoxia Supports Tumor Symbiosis and Hexosamine Biosynthesis in Pancreatic Adenocarcinoma","volume":"110","author":"Guillaumond","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_116","first-page":"174","article-title":"The Effect of HIF-1alpha on Glucose Metabolism, Growth and Apoptosis of Pancreatic Cancerous Cells","volume":"23","author":"He","year":"2014","journal-title":"Asia Pac. J. Clin. Nutr."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"935","DOI":"10.3892\/or.2014.3298","article-title":"Upregulation of Autophagy by Hypoxia-Inducible Factor-1\u03b1 Promotes EMT and Metastatic Ability of CD133+ Pancreatic Cancer Stem-like Cells during Intermittent Hypoxia","volume":"32","author":"Zhu","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1080\/15384047.2016.1139228","article-title":"Hypoxia Regulates ABCG2 Activity through the Activivation of ERK1\/2\/HIF-1\u03b1 and Contributes to Chemoresistance in Pancreatic Cancer Cells","volume":"17","author":"He","year":"2016","journal-title":"Cancer Biol. Ther."},{"key":"ref_119","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_120","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrc.2017.77","article-title":"Tumour Acidosis: From the Passenger to the Driver\u2019s Seat","volume":"17","author":"Corbet","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1042\/bj3430281","article-title":"The Proton-Linked Monocarboxylate Transporter (MCT) Family: Structure, Function and Regulation","volume":"343","author":"Halestrap","year":"1999","journal-title":"Biochem. J."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1186\/s12935-021-02121-5","article-title":"Role of Glutamine and Its Metabolite Ammonia in Crosstalk of Cancer-Associated Fibroblasts and Cancer Cells","volume":"21","author":"Li","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic Anhydrases: Novel Therapeutic Applications for Inhibitors and Activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Strapcova, S., Takacova, M., Csaderova, L., Martinelli, P., Lukacikova, L., Gal, V., Kopacek, J., and Svastova, E. (2020). Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions. Cancers, 12.","DOI":"10.3390\/cancers12082005"},{"key":"ref_125","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":"Casini","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.7150\/ijbs.69526","article-title":"Enhanced Pentose Phosphate Pathway Activity Promotes Pancreatic Ductal Adenocarcinoma Progression via Activating YAP\/MMP1 Axis under Chronic Acidosis","volume":"18","author":"Chen","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"4538","DOI":"10.1038\/onc.2017.71","article-title":"Connexin-43 Channels Are a Pathway for Discharging Lactate from Glycolytic Pancreatic Ductal Adenocarcinoma Cells","volume":"36","author":"Dovmark","year":"2017","journal-title":"Oncogene"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Zeng, S., P\u00f6ttler, M., Lan, B., Gr\u00fctzmann, R., Pilarsky, C., and Yang, H. (2019). Chemoresistance in Pancreatic Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184504"},{"key":"ref_129","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_130","doi-asserted-by":"crossref","unstructured":"Vaish, U., Jain, T., Are, A.C., and Dudeja, V. (2021). Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413408"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"13408","DOI":"10.1038\/s41419-022-05351-1","article-title":"Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma","volume":"13","author":"Zhang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_132","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_133","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_134","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. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1001\/jamaoncol.2019.0892","article-title":"Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial","volume":"5","author":"Murphy","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"eabm9729","DOI":"10.1126\/sciadv.abm9729","article-title":"Pancreatic Tumor Microenvironmental Acidosis and Hypoxia Transform Gold Nanorods into Cell-Penetrant Particles for Potent Radiosensitization","volume":"8","author":"Rauta","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/s41416-018-0246-z","article-title":"Galunisertib plus Gemcitabine vs. Gemcitabine for First-Line Treatment of Patients with Unresectable Pancreatic Cancer","volume":"119","author":"Melisi","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1126\/science.1171362","article-title":"Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer","volume":"324","author":"Olive","year":"2009","journal-title":"Science"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1200\/jco.2012.30.4_suppl.213","article-title":"A Phase Ib Trial of IPI-926, a Hedgehog Pathway Inhibitor, plus Gemcitabine in Patients with Metastatic Pancreatic Cancer","volume":"30","author":"Richards","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_140","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_141","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_142","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"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/1\/61\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:48:06Z","timestamp":1760147286000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/1\/61"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,22]]},"references-count":142,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cancers15010061"],"URL":"https:\/\/doi.org\/10.3390\/cancers15010061","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,22]]}}}