Loss of proton‐sensing TDAG8 increases tumor progression in mouse models of colon cancer
- 1Department of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Switzerland
Abstract
T‐cell death‐associated gene 8 (TDAG8) is a proton‐sensing G‐protein‐coupled receptor that is activated by neutral to acidic extracellular pH. TDAG8 is primarily expressed in leukocytes and leukocyte‐rich tissues, including the spleen, lymph nodes, and thymus. Genome‐wide association studies have identified TDAG8 as a risk gene for inflammatory bowel disease (IBD). Patients with IBD have an increased risk of developing colorectal cancer (CRC), and TDAG8 has been implicated in regulating anti‐tumor immunity. We used the MC38 and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models of CRC to evaluate the effect of TDAG8 deficiency on tumor growth. Tumor development was assessed by measuring size and weight, and tumor tissue was analyzed by immunohistochemistry (IHC), real‐time quantitative polymerase chain reaction (qPCR), flow cytometry, and apurinic/apyrimidinic (AP) site quantification. In the MC38 model, Tdag8‐deficient mice presented a significantly increased tumor burden together with significantly increased numbers of neutrophils and monocytes in tumor tissue compared with wild‐type (WT) mice. In the AOM/DSS model of CRC, Tdag8‐deficient mice exhibited significantly increased tumor size, weight, and number of AP sites compared with WT mice. Additionally, Tdag8‐deficient mice showed a significantly increased number of macrophages in tumor tissue and an elevated CD4+/CD8+ ratio, as confirmed by IHC and flow cytometry. In conclusion, loss of Tdag8 significantly worsened colon cancer progression in mice and correlated with increased infiltration of tumor‐associated phagocytes. These findings suggest that positive allosteric TDAG8 modulators could represent a promising therapeutic strategy for CRC treatment.
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BibTeX
@article{malagola2026loss,
title = {{Loss of proton‐sensing TDAG8 increases tumor progression in mouse models of colon cancer}},
author = {Ermanno Malagola and Yasmine Illi and Anna Bircher and Marijn Wilmink and Rachele F. Malagutti and Solenn Ottié and Cordelia Schuler and Pedro A. Ruiz and Cheryl de Vallière and Klaus Seuwen and Gerhard Rogler and Martin Hausmann},
journal = {Molecular Oncology},
year = {2026},
month = jun,
doi = {10.1002/1878-0261.70283},
url = {https://doi.org/10.1002/1878-0261.70283},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Loss of proton‐sensing TDAG8 increases tumor progression in mouse models of colon cancer
AU - Ermanno Malagola
AU - Yasmine Illi
AU - Anna Bircher
AU - Marijn Wilmink
AU - Rachele F. Malagutti
AU - Solenn Ottié
AU - Cordelia Schuler
AU - Pedro A. Ruiz
AU - Cheryl de Vallière
AU - Klaus Seuwen
AU - Gerhard Rogler
AU - Martin Hausmann
PY - 2026
DA - 2026/06/09
JO - Molecular Oncology
DO - 10.1002/1878-0261.70283
UR - https://doi.org/10.1002/1878-0261.70283
AB - T‐cell death‐associated gene 8 (TDAG8) is a proton‐sensing G‐protein‐coupled receptor that is activated by neutral to acidic extracellular pH. TDAG8 is primarily expressed in leukocytes and leukocyte‐rich tissues, including the spleen, lymph nodes, and thymus. Genome‐wide association studies have identified TDAG8 as a risk gene for inflammatory bowel disease (IBD). Patients with IBD have an increased risk of developing colorectal cancer (CRC), and TDAG8 has been implicated in regulating anti‐tumor immunity. We used the MC38 and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models of CRC to evaluate the effect of TDAG8 deficiency on tumor growth. Tumor development was assessed by measuring size and weight, and tumor tissue was analyzed by immunohistochemistry (IHC), real‐time quantitative polymerase chain reaction (qPCR), flow cytometry, and apurinic/apyrimidinic (AP) site quantification. In the MC38 model, Tdag8‐deficient mice presented a significantly increased tumor burden together with significantly increased numbers of neutrophils and monocytes in tumor tissue compared with wild‐type (WT) mice. In the AOM/DSS model of CRC, Tdag8‐deficient mice exhibited significantly increased tumor size, weight, and number of AP sites compared with WT mice. Additionally, Tdag8‐deficient mice showed a significantly increased number of macrophages in tumor tissue and an elevated CD4+/CD8+ ratio, as confirmed by IHC and flow cytometry. In conclusion, loss of Tdag8 significantly worsened colon cancer progression in mice and correlated with increased infiltration of tumor‐associated phagocytes. These findings suggest that positive allosteric TDAG8 modulators could represent a promising therapeutic strategy for CRC treatment.
SN - 1574-7891
SN - 1878-0261
ER -