Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells
Hawthorne, K. A.; Eng, J. R.; Tsuda, M.; Worth, P. J.; Fields, A. J.; Daniel, C. J.; Nishida, A.; Pelz, C.; Langer, E. M.; Waugh, T. A.; Agritelley, E. S.; Link, J. M.; Sheppard, B. C.; Adey, A. C.; Sears, R. C.
Show abstract
Pancreatic ductal adenocarcinoma (PDAC) progression involves malignant cell state plasticity. Epigenetic changes underlie this plasticity, yet the PDAC cis-regulatory landscape remains understudied. To address this, we profiled 33 primary tumors and 7 metastases from 39 patients with single-cell ATAC-seq, paired with 10 single-cell RNA-seq profiles. We found that epigenetic GATA6+/KRT17+ co-accessibility identifies a classical-basal subtype-intermediate progenitor state (SIP) associated with better clinical outcomes. SIP cells display limited epigenetic reprogramming from premalignant epithelium and retain gastric-intestinal differentiation reminiscent of neoplastic precursors. Lineages without GATA6+/KRT17+ co-accessibility exhibit greater lineage and epithelial-mesenchymal plasticity. Classical PDACs that repress basal gene accessibility activate neural-like progenitor (NRP) and tuft lineage enhancers, whereas basal committed tumors display esophageal transdifferentiation. Compared to SIP, classical-NRP and basal committed tumors have poorer outcomes, and show distinct PD-1/PD-L1 immune proteomic phenotypes and prognostic myofibroblast epigenetic states, respectively. Our work reveals links between lineage reprogramming, EMT, and epigenetic progression in human PDAC.
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