ΔNp63 in healhy and diseased pancreas, with focus on subtypes in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer whose incidence is increasing. As diagnosis often occurs in a late stage, therapeutic options are limited and often palliative. The mechanism of the disease has yet to be completely uncovered, although in recent years molecular subtypes have been described, which may lead to targeted therapy. During this PhD project, we aimed at better diagnosing the different subtypes, focusing on the classical and the basal-like subtypes. We first aimed at finding markers with immunohistochemistry to discriminate between the two subtypes. We describe S100A2 as a strong marker, that is present only in basal-like tumours. One subset of basal-like tumours did not express S100A2, but did express ΔNp63, reportedly a driver for the basal-like subtype. Secondly, we wanted to investigate whether these two subtypes could be inferred based on an HE-staining, by creating an algorithm with AI to distinguish between gland-forming and non-gland-forming structures. We found that the AI-algorithm created could successfully distinguish the subtypes. For our second aim, we wanted to investigate the expression of ΔNp63 in the healthy and diseased pancreas. Using immunohistochemical stainings, we found a rare group of cells that expresses ΔNp63 in the healthy pancreas, which increases in chronic pancreatitis, and is present in a subset of PDACs. With further stainings, we confirmed that these cells are alike basal cells, cells that play a role in regeneration and tumour formation in other organs. We did not find the cells in adult mouse or rat pancreata. Finally, using stainings against ΔNp63, we describe heterotopia of a salivary gland in the pancreas. The embedded tissue showed normal histology of a submandibular gland, and no markers of pancreas were detected. In conclusion, we have described two markers, S100A2 and ΔNp63, to distinguish the basal-like subtype from the classical subtype, together with an AI-algorithm. We describe for the first time ΔNp63+ basal cells in the pancreas, which expand upon damage, and found heterotopic tissue of ΔNp63+ salivary gland in one patient. These data together provide new insights into cell differentiation and plasticity of the healthy and diseased pancreas.

ISBN: 9789461174406

Jaar van publicatie:2022

Trefwoorden:ΔNp63, Pancreas, Pancreatic Ductal Adenocarcinoma, PDAC

Toegankelijkheid:Embargoed