E-cadherin loss in Cd44-positive gastric cells initiates diffuse gastric cancer in a murine model.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41708310.
- Also identified by DOI 10.1136/gutjnl-2025-336182.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
<i>CDH1</i> is commonly mutated in sporadic diffuse gastric cancer (DGC) and germline <i>CDH1</i> mutations underlie most cases of the cancer syndrome hereditary DGC. We aimed to develop mouse models of sporadic and hereditary DGC by inactivation of <i>Cdh1</i> in the mouse stomach. We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the <i>Cd44</i> promoter with a tdTomato reporter. Two models were developed, one with <i>Cdh1</i>-knockout alone (<i>Cd44</i>-Cre/<i>tdTom<sup>loxP/loxP</sup>/Cdh1<sup>loxP/loxP</sup></i> (<i>Cdh1-KO</i>)) and a second more aggressive model with combined <i>Cdh1</i> and <i>Trp53</i> knockout (<i>Cd44</i>-Cre/<i>tdTom<sup>loxP/loxP</sup>/Cdh1<sup>loxP/loxP</sup>/Trp53<sup>loxP/loxP</sup></i> (<i>Cdh1-KO/Trp53-KO</i>)). <i>Cdh1</i> 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 <i>Trp53</i> knockout accelerated cancer development, resulting in pT3 DGC within 3 months. From this point, <i>Cdh1-KO/Trp53-KO</i> 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 <i>Cdh1-KO</i> and <i>Cdh1-KO/Trp53-KO</i> 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. Inactivation of <i>Cdh1</i> alone in <i>Cd44</i>-expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent <i>Trp53</i> inactivation.