{ "abstract": "Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of regulatory protein activity in single cells identified three PDA Developmental Lineages (PDLs), coexisting in virtually all tumors, whose transcriptional states are mechanistically driven by aberrant activation of Master Regulator (MR) proteins associated with gastrointestinal lineages (GLS state), morphogen and EMT pathways (MOS state), and acinar-to-ductal metaplasia (ALS state), respectively. Each PDL is further subdivided into sub-states characterized by low vs. high MAPK pathway activity. This taxonomy was remarkably conserved across multiple cohorts, cell lines, and PDX models, and harmonized with bulk profile analyses. Cross-state plasticity and MR essentiality was confirmed by barcode-based lineage tracing and CRISPR/Cas9 assays, respectively, while MR ectopic expression induced PDL transdifferentiation. Together these data provide a mechanistic foundation for PDA heterogeneity and a roadmap for targeting PDA cellular subtypes.", "abstract_shown": true, "affiliations": [ "DarwinHealth Inc., New York, NY, USA", "Department of Systems Biology, Columbia University, New York, NY, USA", "Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA", "Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA", "Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA", "Klinikum rechts der Isar, II. Medizinische Klinik, Technische Universität München, Munich, Germany", "Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA", "Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA", "SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum Solnavägen 9, Stockholm, Sweden", "Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada", "Princess Margaret Cancer Centre, Toronto, Ontario, Canada", "Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA", "Division of Hematology and Oncology, Columbia University Irving Medical Center and New York Presbyterian Hospital Herbert Irving Pavilion, New York, NY, USA", "PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada", "Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. kenolive@columbia.edu", "Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. kenolive@columbia.edu", "Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. kenolive@columbia.edu", "Biohub, New York, NY, USA. ac2248@cumc.columbia.edu", "Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. ac2248@cumc.columbia.edu", "Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. ac2248@cumc.columbia.edu", "Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. ac2248@cumc.columbia.edu", "Department of Systems Biology, Columbia University, New York, NY, USA. ac2248@cumc.columbia.edu", "Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. ac2248@cumc.columbia.edu" ], "article_type": null, "arxiv": null, "author_total": 27, "authors": [ { "affs": [ 0, 1 ], "name": "Pasquale Laise", "orcid": "0000-0003-1469-4704" }, { "affs": [ 1 ], "name": "Mikko Turunen" }, { "affs": [ 2, 3, 4 ], "name": "Álvaro Curiel‐García", "orcid": "0000-0001-6249-3267" }, { "affs": [ 0, 1 ], "name": "Lorenzo Tomassoni", "orcid": "0000-0002-7720-9166" }, { "affs": [ 5 ], "name": "H. Carlo Maurer" }, { "affs": [ 6, 7 ], "name": "Ela Elyada" }, { "affs": [ 8 ], "name": "Bernhard Schmierer", "orcid": "0000-0002-9082-7022" }, { "affs": [ 1 ], "name": "Jeremy Worley" }, { "affs": [ 1 ], "name": "Jordan S. Kesner", "orcid": "0000-0003-1330-1980" }, { "affs": [ 1 ], "name": "Xiangtian Tan", "orcid": "0009-0001-9808-5959" }, { "affs": [ 1 ], "name": "Ester Calvo Fernández", "orcid": "0000-0001-6307-8452" }, { "affs": [ 1 ], "name": "Yuanqing Xue", "orcid": "0000-0003-1892-6787" }, { "affs": [ 1 ], "name": "Yining Chen" }, { "affs": [ 1 ], "name": "Kelly Wong" }, { "affs": [ 3 ], "name": "Urszula N. Wasko", "orcid": "0009-0006-3029-2202" }, { "affs": [ 1 ], "name": "Somnath Tagore", "orcid": "0000-0001-9603-1263" }, { "affs": [ 1 ], "name": "Alexander L.E. Wang", "orcid": "0000-0003-2829-7398" }, { "affs": [ 9, 10 ], "name": "Sabrina Ge", "orcid": "0000-0002-0242-753X" }, { "affs": [ 11 ], "name": "Alina Cornelia Iuga", "orcid": "0000-0002-2351-8289" }, { "affs": [ 1 ], "name": "Aaron Timothy Griffin", "orcid": "0000-0002-8027-0822" }, { "affs": [ 2, 12 ], "name": "Winston Wong" }, { "affs": [ 2, 12, 4 ], "name": "Gulam Abbas Manji", "orcid": "0000-0001-9817-2414" }, { "affs": [ 0, 1 ], "name": "Mariano J. Alvarez", "orcid": "0000-0002-7503-2491" }, { "affs": [ 9, 13, 10 ], "name": "Faiyaz Notta", "orcid": "0000-0002-5748-3985" }, { "affs": [ 6, 7 ], "name": "David Arthur Tuveson", "orcid": "0000-0002-8017-2712" }, { "affs": [ 14, 15, 16 ], "name": "Kenneth P. Olive", "orcid": "0000-0002-3392-8994" }, { "affs": [ 17, 18, 19, 20, 21, 22 ], "name": "Andrea Califano", "orcid": "0000-0003-4742-3679" } ], "bibtex": "https://research.draconitic.com/paper/f12xqphss7arv.bib", "cited_by": 22, "doi": "10.1038/s41588-026-02714-8", "fulltext_url": null, "id": "f12xqphss7arv", "issns": [ "1061-4036", "1546-1718" ], "landing_url": "https://doi.org/10.1038/s41588-026-02714-8", "language": "en", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2730|Pancreatic and Hepatic Oncology Research" ] ], "openalex": "W7204258842", "pdf_url": "https://www.nature.com/articles/s41588-026-02714-8.pdf", "pmcid": "PMC13553295", "pmid": "42649389", "published": "2026-08-26", "publisher": "Nature Portfolio", "ris": "https://research.draconitic.com/paper/f12xqphss7arv.ris", "sources": [ { "first_seen": "2026-11-05T13:21:05Z", "native_id": "W7204258842", "source": "openalex", "url": "https://doi.org/10.1038/s41588-026-02714-8" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2730|Pancreatic and Hepatic Oncology Research", "subfield": "oncology" } ], "title": "Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer", "title_text": "Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer", "type": "peer-reviewed", "updated_at": "2026-11-07T13:20:57Z", "url": "https://research.draconitic.com/paper/f12xqphss7arv", "venue": "Nature Genetics", "versions": [] }