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. 2025 Mar 24;60(6):837-852.e3.
doi: 10.1016/j.devcel.2024.12.003. Epub 2024 Dec 24.

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

Daniel J Salas-Escabillas  1 , Megan T Hoffman  2 , Sydney M Brender  3 , Jacee S Moore  3 , Hui-Ju Wen  3 , Simone Benitz  3 , Erick T Davis  3 , Daniel Long  3 , Allison M Wombwell  3 , Ella Rose D Chianis  4 , Brittany L Allen-Petersen  4 , Nina G Steele  3 , Rosalie C Sears  5 , Ichiro Matsumoto  6 , Kathleen E DelGiorno  7 , Howard C Crawford  8
Affiliations

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

Daniel J Salas-Escabillas et al. Dev Cell. .

Abstract

Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplasia, which progresses to neoplasia and cancer. Tuft cells (TCs) are chemosensory cells not found in the normal pancreas but arise in cancer precursor lesions and diminish during progression to carcinoma. These metaplastic TCs (mTCs) 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 created a dual recombinase lineage trace model, wherein a pancreas-specific FlpO was used to induce tumorigenesis, while a tuft-cell specific Pou2f3CreERT/+ driver was used to induce expression of a tdTomato reporter. We found that mTCs in carcinoma transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in patients. Using conditional knockout and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this tuft-to-neuroendocrine transition (TNT).

Keywords: cellular plasticity; lineage trace; metaplasia; transdifferentiation.

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Conflict of interest statement

Declaration of interests R.C.S. serves as a Scientific Advisory Board member and consultant for Rappta Therapeutics and has received sponsored research from Cardiff Oncology and AstraZeneca.

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