Messal, H; (2017) Clarifying ductal heterogeneity in pancreas maintenance and PDAC morphogenesis. Doctoral thesis , UCL (University College London).

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	Video Movie 1-wildtype ducts.mp4 Download (31MB)
	Video Movie 2 - KFEKrt19 intercalated duct.mpg Download (11MB)
	Video Movie 3 - KFEKrt19 intraloublar duct.mpg Download (21MB)
	Video Movie 4 - KFEKrt19 interlobular duct.mpg Download (5MB)
	Video Movie 5 - KFEKrt19 main duct.mpg Download (34MB)

Abstract

Despite vast scientific efforts and an immense improvement of our understanding of the regenerative and tumourigenic capacity of pancreatic cells, pancreatic disease remains a major health problem, as reflected in the medical complications and compromised living standard of diabetes patients and the extremely low survival of pancreatic ductal adenocarcinoma (PDAC) patients (Weir et al., 2011, Calafiore et al., 2014, Siegel et al., 2016). Pancreatic duct cells have been a longstanding focus of life sciences. On the one hand they are proposed to contain an adult progenitor population with the plastic potential to give rise to β-cells (Bonner-Weir et al., 2010). On the other hand ducts contain a cell of origin for PDAC (Bailey et al., 2015)(Ferreira et al., manuscript submitted). Duct cells are arranged in an intricate architecture, which is difficult to reconstruct from twodimensional tissue sections. This has hampered understanding of duct cell function and role, particularly in the diseased pancreas. Here, I have developed a technique for rapid molecular interrogation of whole mouse pancreas by three-dimensional (3D) confocal microscopy and employed this tool to address two important questions related to pancreatic disease. Firstly, I determined whether the ductal tree contains an adult progenitor cell and secondly I assessed how transformed cells reshape the ductal tree during early PDAC progression. With the help of genetically engineered mouse (GEM) models I traced the ductal lineage in the adult pancreas and found a continuous low-level supply of acinar cells from terminal duct cells. Additionally, upon damage of the exocrine pancreas, the hepato-pancreatic duct adopted acinar-like characteristics including the production of digestive enzymes. These results suggest a segmental heterogeneous plasticity of cells in the ductal tree. Duct and acinar cells have recently been identified as origins for pancreatic ductal adenocarcinoma (PDAC). Using 3D imaging of GEM models, I assessed early stages in transformation and PDAC development. I found that duct and acinar cells adopted similar cytological properties in the course of transformation, but established lesions of distinct morphology. Furthermore, different ductal segments originated two distinct lesion types: Whereas intralobular and intercalated ducts gave rise to globular lesions, main ducts and interlobular ducts presented exclusively intraductal papillary lesions. Together these results highlight a previously unidentified functional heterogeneity of the pancreas ductal tree.

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