Background & Aims: Epithelial tumors generally resemble the cellular architecture of their tissue of origin. However, this link remains largely unexplored in the pancreas.
Methods: Using Nanostring GeoMx DSP®, Resolve Molecular Cartography® and Nanostring CosMx®, and integration with single cell RNAseq datasets, we mapped the human pancreatic ductal epithelium in non-neoplastic pancreas, and compared it to pancreatic cancer subtypes.
Results: Groups of Keratin-5+ cells among the Pan-Cytokeratin+ cells in the duct have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. In spatial analysis at single cell resolution, the pancreatic duct manifests as a stratified epithelium comprising a basal and four luminal populations; In large ducts, KRT5+ basal (BAS) cells express ∆Np63 while KRT5+ luminal (LUM)-B cells reside supra-basally and are distinct from the common KRT5- LUM-A cells. LUM-C and LUM-D cells pertain to intercalated ducts and ductal glands, respectively. LUM-A and -C cells express gel-forming mucins while LUM-B cells have membrane-bound MUC4 and MUC16. In cancer, BAS and LUM-B signatures associate with the basal-like pancreatic ductal adenocarcinoma (PDAC) and correlate with lower survival but exhibit a mixed spatial pattern with a diffracted gene signature. In contrast, adenosquamous cancers of the pancreas (ASCP) preserve the normal spatially unmixed identity of LUM-B cells and BAS cells.
Conclusion: This study reveals a preservation of the native BAS and LUM-B states in ASCP–with functional differences between the two populations–whereas basal-like PDAC shows a diffracted, spatially mixed pattern.