On the Origin of Pancreatic Cancer: Molecular Tumor Subtypes in Perspective of Exocrine Cell Plasticity

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating type of cancer. While many studies have shed light into the pathobiology of PDAC, the nature of PDAC's cell of origin remains under debate. Studies in adult pancreatic tissue have unveiled a remarkable exocrine cell plasticity including transitional states, mostly exemplified by acinar to ductal cell metaplasia, but also with recent evidence hinting at duct to basal cell transitions. Single-cell RNA sequencing has further revealed intrapopulation heterogeneity among acinar and duct cells. Transcriptomic and epigenomic relationships between these exocrine cell differentiation states and PDAC molecular subtypes have started to emerge, suggesting different ontogenies for different tumor subtypes. This review sheds light on these diverse aspects with particular focus on studies with human cells. Understanding the "masked ball" of exocrine cells at origin of PDAC and leaving behind the binary acinar vs duct cell classification may significantly advance our insights in PDAC biology.

Keywords: Heterogeneity; Metaplasia; Pancreas.

Figure 1

Graphical overview of pancreatic cell plasticity in embryonic development, during normal tissue homeostasis, and in neoplastic transformation. Pancreatic embryonic development is characterized by multipotent progenitor cells expressing PDX1, which further differentiate into tripotent progenitor cells, giving rise to eventually bipotent trunk cells that differentiate into duct and endocrine cells, leaving behind the “tip” cells that give rise to acinar cells. In adult tissue, exocrine cell plasticity is still present, with acinar cells being able to dedifferentiate under stress conditions. In this process, the transcription factor MECOM is upregulated, permitting dedifferentiation and avoiding cell death of acinar cells. During that same stress insult, tuft cells appear but their function is still rather unknown. Plasticity within the ductal and basal cell population is still under debate, and basal cells may even be a subtype of epithelial ductal cells. During neoplastic transformation, in a context of activation of oncogenes such as KRAS, dedifferentiated acinar cells can further give rise to a tumor, most likely of the classical subtype. Duct cells possibly follow another route and presumably give rise to a basal-like subtype that is characterized with worse survival outcome.