{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:11:57Z","timestamp":1791922317383,"version":"4.3.4"},"posted":{"date-parts":[[2025,2,5]]},"group-title":"Cancer Biology","reference-count":96,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment contains hypoxic tissue subdomains and cancer-associated fibroblasts (CAFs) of multiple subtypes that play tumor-promoting and -restraining roles. Here, we demonstrate that hypoxia promotes an inflammatory-like CAF phenotype and that hypoxic CAFs selectively promote epithelial-mesenchymal transition (EMT) in PDAC cancer cells through growth factor-mediated cell crosstalk. By analyzing patient tumor single-cell transcriptomics and conducting an inhibitor screen, we identified IGF-2 and HGF as specific EMT-inducing growth factors produced by hypoxic CAFs. We further found that reactive oxygen species-activated NF-\u03baB cooperates with hypoxia-dependent histone methylation to promote IGF-2 and HGF expression in hypoxic CAFs. In lineage-traced autochthonous PDAC mouse tumors, hypoxic CAFs resided preferentially near hypoxic, mesenchymal cancer cells. However, in subcutaneous tumors engineered with hypoxia fate-mapped CAFs, once-hypoxic re-oxygenated CAFs lacked a spatial correlation with mesenchymal cancer cells. Thus, hypoxia promotes reversible CAF-malignant cell interactions that drive EMT through druggable signaling pathways.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One-sentence summary<\/jats:title>\n                  <jats:p>We show that hypoxic fibroblasts in pancreas cancer leverage histone methylation and ROS-mediated NF-\u03baB activation to produce growth factors that drive epithelial-mesenchymal transition in malignant cells, demonstrating how tumor stromal features cooperate to initiate a signaling process for disease progression.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.30.635486","type":"posted-content","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T10:25:11Z","timestamp":1738751111000},"source":"Crossref","is-referenced-by-count":3,"title":["Hypoxia-induced histone methylation and NF-\u03baB activation in pancreas cancer fibroblasts promote EMT-supportive growth factor secretion"],"prefix":"10.64898","author":[{"given":"Karl M.","family":"Kowalewski","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara J.","family":"Adair","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Talkington","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason J.","family":"Wieder","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Pitarresi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kia","family":"Perez-Vale","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britney","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Biomedical Engineering, Duke University, Durham, NC, 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sepideh","family":"Dolatshahi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalie","family":"Sears","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben Z.","family":"Stanger","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd W.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Lazzara","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22903, USA"},{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041023503435000_2025.01.30.635486v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4172"},{"key":"2026041023503435000_2025.01.30.635486v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.284"},{"key":"2026041023503435000_2025.01.30.635486v1.3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1052132"},{"key":"2026041023503435000_2025.01.30.635486v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.012"},{"key":"2026041023503435000_2025.01.30.635486v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42178-6"},{"key":"2026041023503435000_2025.01.30.635486v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40727-7"},{"key":"2026041023503435000_2025.01.30.635486v1.7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-22-2045"},{"key":"2026041023503435000_2025.01.30.635486v1.8","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0111"},{"key":"2026041023503435000_2025.01.30.635486v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1219555110"},{"key":"2026041023503435000_2025.01.30.635486v1.10","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0775"},{"key":"2026041023503435000_2025.01.30.635486v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.08.007"},{"key":"2026041023503435000_2025.01.30.635486v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.353"},{"key":"2026041023503435000_2025.01.30.635486v1.13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-0454"},{"key":"2026041023503435000_2025.01.30.635486v1.14","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1353"},{"key":"2026041023503435000_2025.01.30.635486v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.025"},{"key":"2026041023503435000_2025.01.30.635486v1.16","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-20-0316"},{"key":"2026041023503435000_2025.01.30.635486v1.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1914915116"},{"key":"2026041023503435000_2025.01.30.635486v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgn216"},{"key":"2026041023503435000_2025.01.30.635486v1.19","doi-asserted-by":"crossref","unstructured":"B. A. Brown et al., A histone methylation-MAPK signaling axis drives durable epithelial-mesenchymal transition in hypoxic pancreatic cancer. Cancer Res, (2024).","DOI":"10.1158\/0008-5472.25964339.v1"},{"key":"2026041023503435000_2025.01.30.635486v1.20","doi-asserted-by":"crossref","unstructured":"B. A. Brown , M. J. Lazzara , Single-cell RNA sequencing reveals microenvironment context-specific routes for epithelial-mesenchymal transition in pancreas cancer cells. bioRxiv, (2023).","DOI":"10.1101\/2023.05.30.542969"},{"key":"2026041023503435000_2025.01.30.635486v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118523"},{"key":"2026041023503435000_2025.01.30.635486v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2016.10.006"},{"key":"2026041023503435000_2025.01.30.635486v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30638-4"},{"key":"2026041023503435000_2025.01.30.635486v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27607-8"},{"key":"2026041023503435000_2025.01.30.635486v1.25","doi-asserted-by":"publisher","DOI":"10.2147\/HP.S52636"},{"key":"2026041023503435000_2025.01.30.635486v1.26","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-1756"},{"key":"2026041023503435000_2025.01.30.635486v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)01181-9"},{"key":"2026041023503435000_2025.01.30.635486v1.28","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2022.02.024"},{"key":"2026041023503435000_2025.01.30.635486v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107701"},{"key":"2026041023503435000_2025.01.30.635486v1.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau5870"},{"key":"2026041023503435000_2025.01.30.635486v1.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw1026"},{"key":"2026041023503435000_2025.01.30.635486v1.32","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317645"},{"key":"2026041023503435000_2025.01.30.635486v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1173-8"},{"key":"2026041023503435000_2025.01.30.635486v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.08.042"},{"key":"2026041023503435000_2025.01.30.635486v1.35","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0601"},{"key":"2026041023503435000_2025.01.30.635486v1.36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162024"},{"key":"2026041023503435000_2025.01.30.635486v1.37","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0710"},{"key":"2026041023503435000_2025.01.30.635486v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.02.007"},{"key":"2026041023503435000_2025.01.30.635486v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110227"},{"key":"2026041023503435000_2025.01.30.635486v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2017.54"},{"key":"2026041023503435000_2025.01.30.635486v1.41","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0094"},{"key":"2026041023503435000_2025.01.30.635486v1.42","doi-asserted-by":"publisher","DOI":"10.3892\/or.2020.7600"},{"key":"2026041023503435000_2025.01.30.635486v1.43","unstructured":"T. N. Ashley Mello , Yusoo Lee , Katelyn L. Donahue , Jinju Li , Arvind Rao , Eileen S. Carpenter , Howard C. Crawford , Marina Pasca di Magliano , Kyoung Eun Lee , Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer. Biorxiv, (2022)."},{"key":"2026041023503435000_2025.01.30.635486v1.44","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1158\/0008-5472.CAN-22-2316","article-title":"Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell-Derived Cytokines","volume":"83","year":"2023","journal-title":"Cancer Res"},{"key":"2026041023503435000_2025.01.30.635486v1.45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002256"},{"key":"2026041023503435000_2025.01.30.635486v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/nature06905"},{"key":"2026041023503435000_2025.01.30.635486v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELS.2015.12.004"},{"key":"2026041023503435000_2025.01.30.635486v1.48","doi-asserted-by":"publisher","DOI":"10.1002\/iid3.523"},{"key":"2026041023503435000_2025.01.30.635486v1.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2013644117"},{"key":"2026041023503435000_2025.01.30.635486v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40314-w"},{"key":"2026041023503435000_2025.01.30.635486v1.51","first-page":"2628","article-title":"Upregulation of macrophage migration inhibitory factor promotes tumor metastasis and correlates with poor prognosis of pancreatic ductal adenocarcinoma","volume":"40","year":"2018","journal-title":"Oncol Rep"},{"key":"2026041023503435000_2025.01.30.635486v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0292-x"},{"key":"2026041023503435000_2025.01.30.635486v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21246-9"},{"key":"2026041023503435000_2025.01.30.635486v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0667-5"},{"key":"2026041023503435000_2025.01.30.635486v1.55","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-0876"},{"key":"2026041023503435000_2025.01.30.635486v1.56","unstructured":"(!!! INVALID CITATION !!!)."},{"key":"2026041023503435000_2025.01.30.635486v1.57","unstructured":"K. A. Janes , M. J. Lazzara , Systems Biology of the Cancer Cell. Annu Rev Biomed Eng, (2024)."},{"key":"2026041023503435000_2025.01.30.635486v1.58","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.169599"},{"key":"2026041023503435000_2025.01.30.635486v1.59","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4721"},{"key":"2026041023503435000_2025.01.30.635486v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2016.08.018"},{"key":"2026041023503435000_2025.01.30.635486v1.61","doi-asserted-by":"publisher","DOI":"10.3727\/096368912X657954"},{"key":"2026041023503435000_2025.01.30.635486v1.62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1801348115"},{"key":"2026041023503435000_2025.01.30.635486v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.02.014"},{"key":"2026041023503435000_2025.01.30.635486v1.64","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00409-10"},{"key":"2026041023503435000_2025.01.30.635486v1.65","doi-asserted-by":"crossref","unstructured":"H. Wu et al., Lactate dehydrogenases amplify reactive oxygen species in cancer cells in response to oxidative stimuli. Signal Transduct Target Ther 6, 242 (2021).","DOI":"10.1038\/s41392-021-00595-3"},{"key":"2026041023503435000_2025.01.30.635486v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.08.018"},{"key":"2026041023503435000_2025.01.30.635486v1.67","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00204-12"},{"key":"2026041023503435000_2025.01.30.635486v1.68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912493107"},{"key":"2026041023503435000_2025.01.30.635486v1.69","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3478"},{"key":"2026041023503435000_2025.01.30.635486v1.70","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00179-X"},{"key":"2026041023503435000_2025.01.30.635486v1.71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.23.12258"},{"key":"2026041023503435000_2025.01.30.635486v1.72","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12412-1"},{"key":"2026041023503435000_2025.01.30.635486v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.06.017"},{"key":"2026041023503435000_2025.01.30.635486v1.74","doi-asserted-by":"publisher","DOI":"10.1016\/j.cobme.2019.11.002"},{"key":"2026041023503435000_2025.01.30.635486v1.75","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04321-2"},{"key":"2026041023503435000_2025.01.30.635486v1.76","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1299"},{"key":"2026041023503435000_2025.01.30.635486v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11960"},{"key":"2026041023503435000_2025.01.30.635486v1.78","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2014.2794"},{"key":"2026041023503435000_2025.01.30.635486v1.79","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1824"},{"key":"2026041023503435000_2025.01.30.635486v1.80","doi-asserted-by":"crossref","unstructured":"G. Werba et al., Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment. Nat Commun 14, 797 (2023).","DOI":"10.1038\/s41467-023-36296-4"},{"key":"2026041023503435000_2025.01.30.635486v1.81","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.04.011"},{"key":"2026041023503435000_2025.01.30.635486v1.82","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-1212"},{"key":"2026041023503435000_2025.01.30.635486v1.83","doi-asserted-by":"crossref","unstructured":"L. Wang et al., Targeted delivery of miR-99b reprograms tumor-associated macrophage phenotype leading to tumor regression. J Immunother Cancer 8, (2020).","DOI":"10.1136\/jitc-2019-000517"},{"key":"2026041023503435000_2025.01.30.635486v1.84","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0403-0"},{"key":"2026041023503435000_2025.01.30.635486v1.85","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04437-2"},{"key":"2026041023503435000_2025.01.30.635486v1.86","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0235573"},{"key":"2026041023503435000_2025.01.30.635486v1.87","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-2562"},{"key":"2026041023503435000_2025.01.30.635486v1.88","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2016.06.005"},{"key":"2026041023503435000_2025.01.30.635486v1.89","doi-asserted-by":"crossref","unstructured":"G. Gut , M. D. Herrmann , L. Pelkmans , Multiplexed protein maps link subcellular organization to cellular states. Science 361, (2018).","DOI":"10.1126\/science.aar7042"},{"key":"2026041023503435000_2025.01.30.635486v1.90","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.06.006"},{"key":"2026041023503435000_2025.01.30.635486v1.91","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-021-04344-9"},{"key":"2026041023503435000_2025.01.30.635486v1.92","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.01.040"},{"key":"2026041023503435000_2025.01.30.635486v1.93","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"2026041023503435000_2025.01.30.635486v1.94","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr260"},{"key":"2026041023503435000_2025.01.30.635486v1.95","doi-asserted-by":"crossref","unstructured":"P. J. Myers , S. H. Lee , M. J. Lazzara , Mechanistic and Data-Driven Models of Cell Signaling: Tools for Fundamental Discovery and Rational Design of Therapy. Curr Opin Syst Biol 28, (2021).","DOI":"10.1016\/j.coisb.2021.05.010"},{"key":"2026041023503435000_2025.01.30.635486v1.96","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2021.06.043"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.01.30.635486","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T06:50:47Z","timestamp":1775890247000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.01.30.635486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,5]]},"references-count":96,"URL":"https:\/\/doi.org\/10.1101\/2025.01.30.635486","relation":{},"subject":[],"published":{"date-parts":[[2025,2,5]]},"subtype":"preprint"}}