Abstract PO-059: Understanding the lineage of metaplastic tuft cells in the progression of PDA

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is unique as it is marked by a dramatic increase in the collagen deposition tumor microenvironment. This microenvironment in pancreatic tumors is composed of immune cells and reactive fibroblasts, with the tumor cells themselves comprising only a small proportion of the overall mass. Nearby normal epithelial tissue is also reactive, undergoing a transdifferentiation event known as acinar-to-ductal metaplasia (ADM), where normal acinar cells are replaced by metaplastic duct-like structures. Collectively neoplastic and metaplastic epithelium orchestrate the immune and fibrotic response, and understanding how the pancreatic epithelia communicate to the microenvironment may lead to more effective clinical treatments. Metaplastic tuft cells (MTCs) are a specialized subset of the 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 more than 60 years ago. They are characterized by the “tuft” of microvilli reaching into the lumen and, only recently, studies have 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. 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. MTCs also express other markers outside of the taste sensing proteins, including POU2f3/SKN-1alpha, and DCLK1. 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 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 tuft cells can transdifferentiate into neuroendocrine-like cells during PDA progression. Neuroendocrine (NE) cells are found in aggressive cancers such as prostate and small cell lung cancer. They are characterized by markers such as Synaptophysin (SYP), as well as an upregulation of MYC which has been found to be more aggressive in different cancers. Rosalie Sears, at the Oregon Health and Science University, a specialist of MYC function in PDA, has shown that NE cells in the pancreas not only originate from acinar cells, where MTCs originate but whose presence is associated with poor survival and resistance to treatment in PDA. She has also shown that MYC plays a key role in the regulation of NE cells in PDA. Through my dissertation research, I will investigate tuft to NE-like transdifferentiation and its role in PDA progression. Citation Format: Daniel J. Salas-Escabillas, Megan Hoffman, Howard C. Crawford. Understanding the lineage of metaplastic tuft cells in the progression of PDA [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-059.