Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34087
Title: A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development.
Austin Authors: O'Keefe, Ryan N;Carli, Annalisa L E;Baloyan, David;Chisanga, David;Shi, Wei;Afshar-Sterle, Shoukat ;Eissmann, Moritz F ;Poh, Ashleigh R;Pal, Bhupinder;Seillet, Cyril;Locksley, Richard M;Ernst, Matthias ;Buchert, Michael 
Affiliation: Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Bundoora, Australia.
Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.;Department of Medical Biology, University of Melbourne, Melbourne, Australia.
Department of Medicine, University of California San Francisco, San Francisco, USA.;Howard Hughes Medical Institute, University of California San Francisco, San Francisco, USA.
Issue Date: 28-Oct-2023
Date: 2023
Publication information: Nature Communications 2023-10-28; 14(1)
Abstract: Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.
URI: https://ahro.austin.org.au/austinjspui/handle/1/34087
DOI: 10.1038/s41467-023-42215-4
ORCID: 0000-0002-8527-2165
0000-0003-0312-1097
0000-0002-0421-3957
0000-0002-2855-0616
0000-0001-8375-4753
0000-0002-0941-8679
0000-0002-5468-6867
0000-0002-6399-1177
0000-0003-2672-0148
Journal: Nature Communications
Start page: 6872
PubMed URL: 37898600
ISSN: 2041-1723
Type: Journal Article
Subjects: Interleukin-13/metabolism
Stomach Neoplasms/pathology
Lymphocytes/metabolism
Hyperplasia/metabolism
Metaplasia/metabolism
Appears in Collections:Journal articles

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