Abstract C066: Metaplastic tuft cells transdifferentiate into metaplastic neuroendocrine cells as pancreatic cancer progresses into late stage carcinoma

Abstract

Abstract Progression of pancreatic disease is in part driven by the transdifferentiation of acinar cells into metaplastic ducts in the pancreas. Metaplastic tuft cells (MTCs) are a specialized subset of the metaplastic epithelium that have the potential to drive tumor progression through communication with the microenvironment and modulate PDA progression. Also known as solitary chemosensory cells, tuft cells were first discovered in rodent luminal surfaces, including the nose, stomach, intestine, and bladder, more than 60 years ago. They are characterized by the “tuft” of microvilli reaching into the lumen and, only recently, have studies started to determine the role of normal tuft cells in different organs. These studies determined that tuft cells have different roles depending on the organ in which they reside. Tuft cells are found in several different organs during normal development; however, studies have shown that tuft cells are not present in a normal pancreas. MTCs are only present in the pancreas in PanINs during PDA progression in both humans and mice. Furthermore, the population of MTCs in the pancreas disappears as PDA progresses into invasive carcinoma when using canonical markers of tuft cells. We know little about the role of MTCs in the pancreas, but prior studies have suggested their role as a progenitor cell during PDA. However, these studies do not exclusively mark MTCs during their genesis in a progressive model to of PDA due to a lack of mouse model as well as the complexity of culturing them ex vivo. We have generated a unique dual recombinase mouse model to drive lineage tracing of MTCs during PDA, and our data to suggests that MTCs are not disappearing as PDA progresses but can transdifferentiate into metaplastic neuroendocrine cells. Citation Format: Daniel J. Salas-Escabillas, Jacee Moore, Dan Long, Megan Hoffman, Don Rempinski, Nina Steele, Howard Crawford. Metaplastic tuft cells transdifferentiate into metaplastic neuroendocrine cells as pancreatic cancer progresses into late stage carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C066.