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PDACs have been extensively profiled at advanced stages, and in advanced disease the tumor microenvironment is a major determinant that critically shapes patient outcomes. Since the molecular events occurring prior to invasive growth remain poorly understood, we aimed to investigate changes in the precancerous epithelium and its surrounding niche.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We acquired time-resolved, single-cell transcriptomic (scRNAseq), and accessible-chromatin data from human pluripotent stem cell-derived pancreatic duct-like organoids (PDLO) inducibly expressing KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      and from various niche cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Analysis of the pure epithelium already revealed key signatures of matrix remodeling and inflammation-related signaling upon few days of KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      expression. Machine learning captured KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      -dependent transcriptomic classifiers with high prediction accuracy and niche preparatory relevance. Various co-culture approaches followed by scRNAseq and functional validation, including T-cell microfluidics, demonstrated that the KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      -induced PDLO-secretome activates pancreatic stellate cells (PaSCs) and protects precancerous organoids from T cell infiltration. Additional,\n                      <jats:italic>in silico<\/jats:italic>\n                      \u00a0approaches reconstructed a virtual pancreatic (pre)cancerous space to profile cell\u2013cell interactions between PDLOs and niche cells. TNF\u03b1 emerged as a top-ranked ligand and was functionally validated to mediate T-cell shielding and PaSC activation. Cyst fluid from 80 prospectively sampled Intraductal Papillary Mucinous Neoplasm (IPMNs) \u2013well-known cystic PDAC precursor lesions\u2013 showed a stepwise TNF\u03b1 rise across LGD (low-grade), HGD (high-grade), and IC (invasive cancer).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study reveals that oncogenic KRAS orchestrates niche-preparatory programs that precede PDAC formation and highlight a T cell exclusion program governed by epithelial-derived TNF\u03b1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-025-02541-1","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T08:23:48Z","timestamp":1770107028000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An oncogenic KRAS-driven secretome involving TNF\u03b1 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The isolation of PBMCs from healthy donors was approved by the Ethics Commission of Ulm University (#460\/23). The isolation of pancreatic fibroblasts from healthy wild-type mice was performed at the Cancer Research UK Manchester Institute, University of Manchester (CRUK MI) under a UK Home Office License and in accordance with the \u2018Animal (Scientific Procedures) Act of 1986\u2019 under Project License Number PP0429273 subject to review by the Animal Welfare and Ethical Review Body of CRUK MI. Human pancreatic tissue was obtained from donors who had provided written informed consent under the broad-consent framework of the Center for Personalized Medicine, University Hospital Ulm (State of Baden-W\u00fcrttemberg). All animal care and procedures followed German legal regulations and were approved by the governmental review board of the state of Baden-W\u00fcrttemberg (permission #: 1313, 1590, O.195\u201311, O.195\u201319). Archived pancreata isolated at the indicated time points from KC mice (\n                      LSL-Kras\n                      \n                        G12D\/\n                        +\n                      \n                      (K);\n                      Ptf1a\n                      \n                        Cre\/\n                        +\n                      \n                      (C)) were used to visualize TNF\u03b1 expression via RNA scope. The EMI-IPMN and INCITE study were approved from the institution's ethics committee (number 67\/INT\/2019 and CET302-2024, respectively) for patient's enrollment and all the patients signed informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A.K. reports personal fees from the Falk foundation, Sanofi and Amgen outside the submitted work. No disclosures were reported by the other authors.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"29"}}