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

Laise P, Turunen M, Curiel-Garcia A, Tomassoni L, Maurer HC, Elyada E, Schmierer B, Worley J, Kesner J, Tan X, Fernandez EC, Xue Y, Chen Y, Wong K, Wasko UN, Tagore S, Wang ALE, Ge S, Iuga AC, Griffin AT, Wong W, Manji GA, Alvarez MJ, Notta F, Tuveson DA, Olive KP, Califano A

Nat. Genet. 58 (9) 2226-2239 [2026-09-00; online 2026-08-26]

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.

CRISPR Functional Genomics [Collaborative]

PubMed 42649389

DOI 10.1038/s41588-026-02714-8

Crossref 10.1038/s41588-026-02714-8

pmc: PMC13553295
pii: 10.1038/s41588-026-02714-8