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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Elsevier
2025-06-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725005054 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Giovanni Valenti |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-498db2e3c87945b49cef6fe53cdda5e2 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-498db2e3c87945b49cef6fe53cdda5e22025-08-20T02:26:11ZengElsevierCell Reports2211-12472025-06-0144611573410.1016/j.celrep.2025.115734Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progressionGiovanni Valenti0Pasquale Laise1Feijing Wu2Ryota Takahashi3Tuo Ruan4Alessandro Vasciaveo5Zhengyu Jiang6Hiroki Kobayashi7Masaki Sunagawa8Moritz Middelhoff9Henrik Nienhüser10Na Fu11Ermanno Malagola12Osmel Companioni13Yoku Hayakawa14Alina C. Iuga15Andrea Califano16Timothy C. Wang17Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADepartment of Systems Biology, Columbia University, New York, NY, USA; DarwinHealth, Inc., New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADepartment of Systems Biology, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USAKlinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, TU Munich, Munich, GermanyDivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USAGraduate School of Medicine, Department of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Pathology and Cell Biology, Columbia University, New York, NY, USADepartment of Systems Biology, Columbia University, New York, NY, USA; DarwinHealth, Inc., New York, NY, USA; Chan Zuckerberg Biohub New York, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USADivision of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725005054CP: Cancer |
| spellingShingle | 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 Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression Cell Reports CP: Cancer |
| title | Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression |
| title_full | Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression |
| title_fullStr | Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression |
| title_full_unstemmed | Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression |
| title_short | Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression |
| title_sort | regulatory network analysis of dclk1 gene expression reveals a tuft cell ilc2 axis that inhibits pancreatic tumor progression |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725005054 |
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