Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression
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<sup>+</sup> ADM-like cells sustaining and Dclk1<sup>+</sup> tuft-like cells restraining tumor progression. The generation of Dclk1<sup>+</sup> 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<sup>+</sup> tuft-like cells release angiotensinogen to restrain tumor progression. Overall, our study defines pancreatic Dclk1<sup>+</sup> cells and unveils a protective tuft cell-ILC2 axis against pancreatic neoplasia.
Authors
- Henrik Nienhüser (ORCID: https://orcid.org/0000-0002-0475-9538)
- Moritz Middelhoff (ORCID: https://orcid.org/0000-0001-8425-3985)
- Tuo Ruan
- Alina C. Iuga (ORCID: https://orcid.org/0000-0002-2351-8289)
- Na Fu (ORCID: https://orcid.org/0000-0002-0563-9925)
- Pasquale Laise (ORCID: https://orcid.org/0000-0003-1469-4704)
- Andrea Califano (ORCID: https://orcid.org/0000-0003-4742-3679)
- Ermanno Malagola (ORCID: https://orcid.org/0000-0001-9294-3097)
- Osmel Companioni (ORCID: https://orcid.org/0000-0001-6605-945X)
- Hiroki Kobayashi (ORCID: https://orcid.org/0000-0002-1717-4870)
- Feijing Wu (ORCID: https://orcid.org/0000-0001-9198-7960)
- Yoku Hayakawa (ORCID: https://orcid.org/0000-0002-3988-2499)
- Alessandro Vasciaveo (ORCID: https://orcid.org/0000-0003-0205-9869)
- Giovanni Valenti (ORCID: https://orcid.org/0000-0002-6223-2072)
- Masaki Sunagawa (ORCID: https://orcid.org/0000-0002-8334-1964)
- Timothy C. Wang (ORCID: https://orcid.org/0000-0001-5730-3019)
- Ryota Takahashi (ORCID: https://orcid.org/0000-0001-7886-8481)
- Zhengyu Jiang (ORCID: https://orcid.org/0000-0002-3235-0326)
Institutions
- Columbia University Irving Medical Center (US)
- TUM Klinikum (DE)
- LMU Klinikum (DE)
- DarwinHealth (United States) (US)
- The University of Tokyo (JP)
- Columbia University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1016/j.celrep.2025.115734
- Citations
- 2
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.59