Extra-lineage tissue programs define the transcription states of human pancreatic cancer

Cancers acquire alternate transcriptional states as they evolve, but the origins, timing and determinants of this plasticity are poorly understood in many tumours. We investigated the transcriptional states of pancreatic cancer by integrating [~]1000 tumour-enriched genomes and transcriptomes from 464 patients combined with scRNA-seq, multiome profiling, and spatial proteomics. Four epithelial states covering the spectrum of lineage plasticity were identified (Classical-1, Classical-2, Basal-1, Basal-2). Comparing these states to normal and pan-cancer human single cell atlases showed each state reflects distinct tissue programs found in other malignancies. Single cell analysis uncovered that the main transcription state of this disease (Classical-1) emerges before KRAS mutations. Spatial proteomics from patients and cancer-free donors showed that the Classical-1 program emerges during acinar-to-ductal metaplasia, and also unexpectedly, in normal ducts without disrupting their morphology. Overall, these findings link the extensive lineage plasticity potential of this organ to the origins of the transcriptional states.