Abstract B052: Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is predicted to become the second leading cause of cancer-related death in 2025 and has a 5-year survival rate of only 11%. Progression of the 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 has 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 of PDA due to a lack of a mouse model as well as the complexity of culturing them ex vivo. We have generated a unique mouse model to drive lineage tracing of MTCs during PDA, and I have preliminary data to suggest that MTCs are not disappearing as PDA progresses but can transdifferentiate into another cell type that is correlated with lower survival in patients. Citation Format: Daniel Salas-Escabillas, Howard Crawford, Megan Hoffman. Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B052.