E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model

Abstract

Background CDH1 is commonly mutated in sporadic diffuse gastric cancer (DGC) and germline CDH1 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 Cdh1 in the mouse stomach. Design We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the Cd44 promoter with a tdTomato reporter. Two models were developed, one with Cdh1-knockout alone (Cd44-Cre/tdTomloxP/loxP/Cdh1loxP/loxP (Cdh1-KO)) and a second more aggressive model with combined Cdh1 and Trp53 knockout (Cd44-Cre/tdTomloxP/loxP/Cdh1loxP/loxP/Trp53loxP/loxP (Cdh1-KO/Trp53-KO)). Results Cdh1 inactivation alone led to multiple foci of in situ (pTis) signet ring cells (SRCs) within 1week of induction and intramucosal DGC (stage pT1a) within 2months. By 9months, 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 Trp53 knockout accelerated cancer development, resulting in pT3 DGC within 3months. From this point, Cdh1-KO/Trp53-KO 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 Cdh1-KO and Cdh1-KO/Trp53-KO 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 Cdh1 alone in Cd44-expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent Trp53 inactivation.