Abstract C067: Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, diminishing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) function to suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we have created a lineage tracing model that uses a tamoxifen-inducible tuft-cell specific Pou2f3CreERT/+ driver to induce transgene expression, including the lineage tracer tdTomato or the oncogene Myc. mTC lineage trace models of pancreatic neoplasia and carcinoma were used to follow mTC fate. We found that mTCs, in the carcinoma model, transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in PDA patients. Using conditional knock-out and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this Tuft-to- Neuroendocrine-Transition (TNT). Citation Format: Daniel J. Salas-Escabillas, Megan T. Hoffman, Sydney M. Brender, Jacee S. Moore, Hui-Ju Wen, Simone Benitz, Erick T. Davis, Daniel Long, Allison Wombwell, Nina G. Steele, Brittany Allen-Petersen, Rosalie C. Sears, Ichiro Matsumoto, Kathleen E. DelGiorno, Howard C. Crawford. Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C067.