Luminal-basal stratification of the native human pancreatic duct is differentially represented in pancreatic cancers.

A resemblance of pancreatic tumours to their native tissue architecture remains largely unexplored, while it may reveal novel insights into healthy and diseased tissue. This study aims at generating a spatially resolved map of human pancreatic duct cell populations in the native tissue and in tumours, that is, pancreatic ductal adenocarcinoma (PDAC) and adenosquamous carcinoma of the pancreas (ASCP). New datasets were acquired with several spatial transcriptomics platforms integrated with public single-cell RNAseq datasets and validated by multiplex immunofluorescence. Cell lines and primary human cell cultures were genetically manipulated. Groups of Keratin-5+ cells in larger ducts have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. At single cell resolution, this group comprises ∆Np63+ basal cells (BAS) and ∆Np63- supra-basally residing luminal-B cells (LUM-B). The latter express previously unreported MUC4 and MUC16 and are distinct from other luminal cells in the ducts. In cancer, BAS and LUM-B signatures associate with basal-like (BL) PDAC and correlate with lower survival. However, PDAC exhibits a random spatial pattern and fragmented native expression programmes while ASCP preserves the identity of LUM-B and BAS in a spatially unmixed pattern. ∆Np63 drives cell plasticity to BAS, conserved from the native tissue to cancer. Spatially distinct duct cell populations are revealed, and the extent of preservation of the native cell identities in pancreatic cancer underpins distinct tumour identities. This warrants separate consideration in research and therapy.