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

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

doi:10.1016/j.devcel.2024.12.003

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

Dev Cell. 2024 Dec 19:S1534-5807(24)00725-1. doi: 10.1016/j.devcel.2024.12.003. Online ahead of print.

Authors

Daniel J Salas-Escabillas¹, Megan T Hoffman², Sydney M Brender³, Jacee S Moore³, Hui-Ju Wen³, Simone Benitz³, Erick T Davis³, Daniel Long³, Allison M Wombwell³, Ella Rose D Chianis⁴, Brittany L Allen-Petersen⁴, Nina G Steele³, Rosalie C Sears⁵, Ichiro Matsumoto⁶, Kathleen E DelGiorno⁷, Howard C Crawford⁸

Affiliations

¹ Cancer Biology, University of Michigan, Ann Arbor, MI, USA; Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA.
² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA.
⁴ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
⁵ Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
⁶ Monell Chemical Senses Center, Philadelphia, PA, USA.
⁷ Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁸ Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA. Electronic address: [email protected].

PMID: 39721583
DOI: 10.1016/j.devcel.2024.12.003

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 Pou2f3^CreERT/+ 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.