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Peer-reviewedCC BY-NC-NDNature Genetics

Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer

  • Pasquale Laise1,2
  • Mikko Turunen2
  • Álvaro Curiel‐García3,4,5
  • Lorenzo Tomassoni1,2
  • H. Carlo Maurer6
  • Ela Elyada7,8
  • Bernhard Schmierer9
  • Jeremy Worley2
  • Jordan S. Kesner2
  • Xiangtian Tan2
  • Ester Calvo Fernández2
  • Yuanqing Xue2
15 more authors
  • Yining Chen2
  • Kelly Wong2
  • Urszula N. Wasko4
  • Somnath Tagore2
  • Alexander L.E. Wang2
  • Sabrina Ge10,11
  • Alina Cornelia Iuga12
  • Aaron Timothy Griffin2
  • Winston Wong3,13
  • Gulam Abbas Manji3,13,5
  • Mariano J. Alvarez1,2
  • Faiyaz Notta10,14,11
  • David Arthur Tuveson7,8
  • Kenneth P. Olive15,16,17
  • Andrea Califano18,19,20,21,22,23
23 affiliations
  1. 1DarwinHealth Inc., New York, NY, USA
  2. 2Department of Systems Biology, Columbia University, New York, NY, USA
  3. 3Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
  4. 4Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
  5. 5Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
  6. 6Klinikum rechts der Isar, II. Medizinische Klinik, Technische Universität München, Munich, Germany
  7. 7Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
  8. 8Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA
  9. 9SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum Solnavägen 9, Stockholm, Sweden
  10. 10Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  11. 11Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  12. 12Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  13. 13Division of Hematology and Oncology, Columbia University Irving Medical Center and New York Presbyterian Hospital Herbert Irving Pavilion, New York, NY, USA
  14. 14PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  15. 15Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. [email protected]
  16. 16Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. [email protected]
  17. 17Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. [email protected]
  18. 18Biohub, New York, NY, USA. [email protected]
  19. 19Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. [email protected]
  20. 20Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. [email protected]
  21. 21Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. [email protected]
  22. 22Department of Systems Biology, Columbia University, New York, NY, USA. [email protected]
  23. 23Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{laise2026developmental,
  title = {{Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer}},
  author = {Pasquale Laise and Mikko Turunen and Álvaro Curiel‐García and Lorenzo Tomassoni and H. Carlo Maurer and Ela Elyada and Bernhard Schmierer and Jeremy Worley and Jordan S. Kesner and Xiangtian Tan and Ester Calvo Fernández and Yuanqing Xue and Yining Chen and Kelly Wong and Urszula N. Wasko and Somnath Tagore and Alexander L.E. Wang and Sabrina Ge and Alina Cornelia Iuga and Aaron Timothy Griffin and Winston Wong and Gulam Abbas Manji and Mariano J. Alvarez and Faiyaz Notta and David Arthur Tuveson and Kenneth P. Olive and Andrea Califano},
  journal = {Nature Genetics},
  year = {2026},
  month = aug,
  doi = {10.1038/s41588-026-02714-8},
  url = {https://doi.org/10.1038/s41588-026-02714-8},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer
AU  - Pasquale Laise
AU  - Mikko Turunen
AU  - Álvaro Curiel‐García
AU  - Lorenzo Tomassoni
AU  - H. Carlo Maurer
AU  - Ela Elyada
AU  - Bernhard Schmierer
AU  - Jeremy Worley
AU  - Jordan S. Kesner
AU  - Xiangtian Tan
AU  - Ester Calvo Fernández
AU  - Yuanqing Xue
AU  - Yining Chen
AU  - Kelly Wong
AU  - Urszula N. Wasko
AU  - Somnath Tagore
AU  - Alexander L.E. Wang
AU  - Sabrina Ge
AU  - Alina Cornelia Iuga
AU  - Aaron Timothy Griffin
AU  - Winston Wong
AU  - Gulam Abbas Manji
AU  - Mariano J. Alvarez
AU  - Faiyaz Notta
AU  - David Arthur Tuveson
AU  - Kenneth P. Olive
AU  - Andrea Califano
PY  - 2026
DA  - 2026/08/26
JO  - Nature Genetics
DO  - 10.1038/s41588-026-02714-8
UR  - https://doi.org/10.1038/s41588-026-02714-8
AB  - 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.
SN  - 1061-4036
SN  - 1546-1718
ER  -