A Luminal-Basal Stratification of the Native Human Pancreatic Duct is Differentially Represented in Pancreatic Cancers

Abstract

BackgroundA resemblance of pancreatic tumors to their native tissue architecture remains largely unexplored, while it may reveal novel insights into the healthy and diseased tissue. ObjectiveThis study aims at generating a spatially resolved map of human pancreatic duct cell populations in the native tissue and in tumors, i.e. pancreatic ductal adenocarcinoma (PDAC) and adenosquamous cancer of the pancreas (ASCP). DesignNew datasets were acquired with several spatial transcriptomics platforms and were integrated with public single-cell RNAseq datasets and validated by multiplex immunofluorescence. Cell lines and primary human cell cultures were genetically manipulated. ResultsGroups 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 {Delta}Np63+ basal cells (BAS) and {Delta}Np63- supra-basally residing luminal-B cells (LUM-B). The latter express previously unreported MUC4 and MUC16. Additionally, we identified three other luminal cell populations in the ducts (LUM-A, -C, -D). 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 programs while ASCP preserve the identity of LUM-B and BAS in a spatially unmixed pattern. {Delta}Np63 drives cell plasticity to BAS, conserved from the native tissue to cancer. ConclusionSpatially distinct duct cell populations are revealed, and the extent of preservation of the native cell identities in pancreatic cancer underpins distinct tumor identities. This warrants a separate consideration in research and therapy. What is already known on this topicWhile tumors in the pancreas can exhibit basal-like and squamous features resembling tumors of other tissues, their resemblance to the native duct cells, and possible subpopulations thereof, had not been studied in detail. What this study addsOne basal and four luminal spatially distinct cell populations exist in human pancreatic ducts. These are best conserved in ASCP while PDAC shows loss of the native cell identity program. How this study might affect research, practice or policyOur study demonstrates fundamental differences between the tumor cells of the BL PDAC versus the rare ASCP, highlighting the necessity for a clear distinction between them in research and in tumor-specific treatments. Meanwhile, the research community should acknowledge the spatial and functional heterogeneity of human duct cells, including in their experimental models.