Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression

Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression

Summary: Doublecortin-like kinase 1 (Dclk1) expression identifies cells that are rare in normal pancreas but occur with an increased frequency in pancreatic neoplasia. The identity of these cells has been a matter of debate. We employed Dclk1 reporter mouse models and single-cell RNA sequencing (scR...

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Main Authors: Giovanni Valenti, Pasquale Laise, Feijing Wu, Ryota Takahashi, Tuo Ruan, Alessandro Vasciaveo, Zhengyu Jiang, Hiroki Kobayashi, Masaki Sunagawa, Moritz Middelhoff, Henrik Nienhüser, Na Fu, Ermanno Malagola, Osmel Companioni, Yoku Hayakawa, Alina C. Iuga, Andrea Califano, Timothy C. Wang
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:Cell Reports
Subjects:
CP: Cancer
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725005054
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Summary:Summary: Doublecortin-like kinase 1 (Dclk1) expression identifies cells that are rare in normal pancreas but occur with an increased frequency in pancreatic neoplasia. The identity of these cells has been a matter of debate. We employed Dclk1 reporter mouse models and single-cell RNA sequencing (scRNA-seq) to define Dclk1-expressing cells. In normal pancreas, Dclk1 identifies subsets of ductal, islet, and acinar cells. In pancreatic neoplasia, Dclk1 identifies several cell populations, among which acinar-to-ductal metaplasia (ADM)-like cells and tuft-like cells are predominant. These two populations play opposing roles, with Dclk1+ ADM-like cells sustaining and Dclk1+ tuft-like cells restraining tumor progression. The generation of Dclk1+ tuft-like cells requires the transcription factor SPIB and is sustained by a paracrine loop involving type 2 innate lymphoid cells (ILC2s) and cancer-associated fibroblasts (CAFs) that provide interleukin (IL)-13 and IL-33, respectively. Dclk1+ tuft-like cells release angiotensinogen to restrain tumor progression. Overall, our study defines pancreatic Dclk1+ cells and unveils a protective tuft cell-ILC2 axis against pancreatic neoplasia.
ISSN:2211-1247

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