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bioRxiv · 10.64898/2026.09.28.754674

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.
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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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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.. 2026-09-29. Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells. https://doi.org/10.64898/2026.09.28.754674

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