Abstract
Simple SummaryPancreatic Cancer is a deadly disease, with a dismal prognosis. A better understanding of the molecular alterations that cause the malignant transformation of pancreatic epithelial cells is pivotal to curtail disease incidence and detect the disease early when it can be surgically resected. The culture of pancreatic pre-malignant cells is technically challenging, but a great tool for the study of tumor evolution and early oncogenic alterations. Here, we will describe the isolation of pancreatic acinar cells and its value for the study of tumor initiation, from a technical and historical perspective.The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.
Highlights
Pancreatic adenocarcinoma (PDA) is the most common form of pancreatic cancer, a disease that poses significant therapeutic challenges and accounts for more than 400,000 deaths worldwide [1].The extremely poor survival rate of 9% with a five-year survival rate makes PDA the most lethal among major forms of cancer [2]
Dysplastic lesions are characterized by a distinctive duct-like morphology, which has led to the assumption that PDA arises from the expansion of mutated ductal cells
Consistent with its physiological function in tissue regeneration, acinar-to-ductal metaplasia is supported in part by the re-activation of developmental pathways including the Wnt/β-catenin pathway, which is known to regulate embryonic acinar development [74]. β-catenin stabilization is required for pancreatic regeneration after acinar cell loss [75], and Wnt signaling progressively increases during pancreatic carcinogenesis while acini isolated from β-catenin-deficient mice do not undergo metaplasia ex vivo [76,77]
Summary
Pancreatic adenocarcinoma (PDA) is the most common form of pancreatic cancer, a disease that poses significant therapeutic challenges and accounts for more than 400,000 deaths worldwide [1]. Dysplastic lesions are characterized by a distinctive duct-like morphology, which has led to the assumption that PDA arises from the expansion of mutated ductal cells This notion has been increasingly disputed by several pieces of evidence since the early 1990s. This review will focus on early steps of pancreatic carcinogenesis and will describe the usage of a three-dimensional, organotypic culture of primary pancreatic epithelial cells for the interrogation of molecular alterations causing neoplastic transformation of acinar cells. The value of this approach as an ex vivo model of tumor initiation will be discussed and notable results obtained using this in vitro tool will be presented
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