E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.
[BACKGROUND] is commonly mutated in sporadic diffuse gastric cancer (DGC) and germline mutations underlie most cases of the cancer syndrome hereditary DGC.
APA
Decourtye-Espiard L, Schulpen E, et al. (2026). E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.. Gut. https://doi.org/10.1136/gutjnl-2025-336182
MLA
Decourtye-Espiard L, et al.. "E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.." Gut, 2026.
PMID
41708310
Abstract
[BACKGROUND] is commonly mutated in sporadic diffuse gastric cancer (DGC) and germline mutations underlie most cases of the cancer syndrome hereditary DGC.
[OBJECTIVE] We aimed to develop mouse models of sporadic and hereditary DGC by inactivation of in the mouse stomach.
[DESIGN] We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the promoter with a tdTomato reporter. Two models were developed, one with -knockout alone (-Cre/ ()) and a second more aggressive model with combined and knockout (-Cre/ ()).
[RESULTS] inactivation alone led to multiple foci of in situ (pTis) signet ring cells (SRCs) within 1 week of induction and intramucosal DGC (stage pT1a) within 2 months. By 9 months, 50% of mice had developed advanced (pT3) DGC. The morphology of most gastric carcinomas was comparable to human DGC, exhibiting poorly cohesive SRC and poorly differentiated cells. Additional knockout accelerated cancer development, resulting in pT3 DGC within 3 months. From this point, mice frequently developed thymic lymphomas and soft tissue sarcomas. DNA sequencing did not find evidence of additional genetic events necessary for cancer progression in either model. Organoids derived from and mice showed a disrupted morphology with SRCs displaced out of the epithelial plane. Transcriptional changes associated with processes including cell-to-cell adhesion, interaction with the actin cytoskeleton and NF-κB signalling were observed.
[CONCLUSION] Inactivation of alone in -expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent inactivation.
[OBJECTIVE] We aimed to develop mouse models of sporadic and hereditary DGC by inactivation of in the mouse stomach.
[DESIGN] We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the promoter with a tdTomato reporter. Two models were developed, one with -knockout alone (-Cre/ ()) and a second more aggressive model with combined and knockout (-Cre/ ()).
[RESULTS] inactivation alone led to multiple foci of in situ (pTis) signet ring cells (SRCs) within 1 week of induction and intramucosal DGC (stage pT1a) within 2 months. By 9 months, 50% of mice had developed advanced (pT3) DGC. The morphology of most gastric carcinomas was comparable to human DGC, exhibiting poorly cohesive SRC and poorly differentiated cells. Additional knockout accelerated cancer development, resulting in pT3 DGC within 3 months. From this point, mice frequently developed thymic lymphomas and soft tissue sarcomas. DNA sequencing did not find evidence of additional genetic events necessary for cancer progression in either model. Organoids derived from and mice showed a disrupted morphology with SRCs displaced out of the epithelial plane. Transcriptional changes associated with processes including cell-to-cell adhesion, interaction with the actin cytoskeleton and NF-κB signalling were observed.
[CONCLUSION] Inactivation of alone in -expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent inactivation.