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Uncertain Beginnings: Acinar and Ductal Cell Plasticity in the Development of Pancreatic Cancer

Journal

Publisher

ELSEVIER INC
DOI: 10.1016/j.jcmgh.2021.07.014

Keywords

acinar cells; ductal cells; cell-of-origin; pancreatic cancer; IPMN; PanIN; lineage-tracing; mouse models

Funding

  1. Prevent Cancer Foundation Fellowship
  2. AACR-Pancreatic Cancer Action Network Pathway to Leadership Award
  3. American Surgical Association Foundation Fellowship Award
  4. Ring Family Foundation
  5. National Cancer Institute [R01CA204228]

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The pancreas contains a high level of cellular plasticity, which can alter cellular identity during injury, regeneration, and repair processes. The cell of origin of pancreatic cancer is difficult to determine, but research suggests that acinar cells may be the most likely origin of intraductal papillary neoplasms and pancreatic intraepithelial neoplasia, while both acinar and ductal cells can undergo malignant transformation into pancreatic ductal adenocarcinoma.
The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant cellular plasticity within the pancreas appears to be exploited in tumorigenesis, with metaplastic, dedifferentiation, and transdifferentiation processes central to the development of pancreatic intraepithelial neoplasia and intraductal papillary neoplasms, precursor lesions to pancreatic ductal adenocarcinoma. In the face of shifting cellular identity, the cell of origin of pancreatic cancer has been difficult to elucidate. However, with the extensive utilization of in vivo lineage-traced mouse models coupled with insights from human samples, it has emerged that the acinar cell is most efficiently able to give rise to both intraductal papillary neoplasms and pancreatic intraepithelial neoplasia but that acinar and ductal cells can undergo malignant transformation to pancreatic ductal adenocarcinoma. In this review, we discuss the cellular reprogramming that takes place in both the normal and malignant pancreas and evaluate the current state of evidence that implicate both the acinar and ductal cell as context-dependent origins of this deadly disease.

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