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

There is broad consensus that the malignant epithelial cells of human pancreatic ductal adenocarcinoma (PDA) comprise multiple, molecularly distinct states. Yet precise characterization of how these are regulated—including their mechanistic determinants, dependencies, plasticity and functional properties—remains elusive. Single-cell master regulator (MR) analysis of multiple PDA cohorts identified malignant cells in three co-existing, molecularly distinct developmental lineage states, with distinct histopathological morphologies and spatial architecture. These include a poorly differentiated lineage driven by epithelial–mesenchymal-transition-related MRs and two well-differentiated states driven by gastrointestinal epithelial development and pancreatic development MRs, respectively. Furthermore, each state comprises two epigenetically distinct substates with low versus high MAPK signaling activity. Barcode-based lineage tracing confirmed both spontaneous and treatment-dependent cross-state plasticity. Furthermore, loss-of-function studies confirmed state-specific MR essentiality, while their ectopic expression effectively reprogrammed cell state, in vitro and in vivo, thus providing a mechanism-based foundation for PDA heterogeneity and a roadmap for pharmacological targeting. The authors apply ARACNe and metaVIPER to published scRNA-seq datasets to characterize pancreatic cancer subtypes, identifying six distinct cell states as well as their mechanistic determinants. Functional experiments in vivo and in vitro demonstrate how these inferred states display plasticity and associate with functional dependencies.

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Publication Details

Journal
Nature Genetics
Published
2026-08-26
DOI
https://doi.org/10.1038/s41588-026-02714-8
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Mikko Turunen, Ester Calvo Fernández, Aaron T. Griffin, Yuanqing Xue et al.
Nature Genetics
Pancreatic and Hepatic Oncology Research
article

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

Mikko Turunen, Ester Calvo Fernández, Aaron T. Griffin, Yuanqing Xue, Bernhard Schmierer, Urszula N. Wasko, Kenneth P. Olive, Xiangtian Tan, Pasquale Laise, Alexander L.E. Wang, Andrea Califano, Faiyaz Notta, Ela Elyada, David A. Tuveson, Sabrina Ge, Somnath Tagore, Lorenzo Tomassoni, Kelly Wong, Jeremy Worley, Alina C. Iuga, Alvaro Curiel-Garcia, Gulam A Manji, Jordan Kesner, Mariano J. Alvarez, Yining Chen, Winston Wong, H. Carlo Maurer
article en

Abstract

There is broad consensus that the malignant epithelial cells of human pancreatic ductal adenocarcinoma (PDA) comprise multiple, molecularly distinct states. Yet precise characterization of how these are regulated—including their mechanistic determinants, dependencies, plasticity and functional properties—remains elusive. Single-cell master regulator (MR) analysis of multiple PDA cohorts identified malignant cells in three co-existing, molecularly distinct developmental lineage states, with distinct histopathological morphologies and spatial architecture. These include a poorly differentiated lineage driven by epithelial–mesenchymal-transition-related MRs and two well-differentiated states driven by gastrointestinal epithelial development and pancreatic development MRs, respectively. Furthermore, each state comprises two epigenetically distinct substates with low versus high MAPK signaling activity. Barcode-based lineage tracing confirmed both spontaneous and treatment-dependent cross-state plasticity. Furthermore, loss-of-function studies confirmed state-specific MR essentiality, while their ectopic expression effectively reprogrammed cell state, in vitro and in vivo, thus providing a mechanism-based foundation for PDA heterogeneity and a roadmap for pharmacological targeting. The authors apply ARACNe and metaVIPER to published scRNA-seq datasets to characterize pancreatic cancer subtypes, identifying six distinct cell states as well as their mechanistic determinants. Functional experiments in vivo and in vitro demonstrate how these inferred states display plasticity and associate with functional dependencies.

Nature Genetics
Ontario Institute for Cancer Research (CA), University of North Carolina at Chapel Hill (US), NewYork–Presbyterian Hospital (US), University of Toronto (CA), Cold Spring Harbor Laboratory (US), Columbia University Irving Medical Center (US), Science for Life Laboratory (SE), Lustgarten Foundation (US), New York Hospital Queens (US), TUM Klinikum (DE), Princess Margaret Cancer Centre (CA), DarwinHealth (United States) (US), Technical University of Munich (DE), Columbia University (US)
National Institutes of Health, Uppsala Multidisciplinary Center for Advanced Computational Science, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 13%
Pancreatic and Hepatic Oncology Research
DOIOpen Access PDFOpenAlex
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