• CDH3, also known as P-Cadherin, is a calcium-dependent cell-cell adhesion glycoprotein belonging to the classical type I cadherin family. Its structure is characterized by five extracellular cadherin repeats (EC1-EC5) that mediate homophilic binding (CDH3-to-CDH3 interaction between adjacent cells), a single-pass transmembrane domain, and a highly conserved cytoplasmic tail. This cytoplasmic domain interacts with catenin proteins (p120-catenin and β-catenin), which bridge the complex to the actin cytoskeleton, enabling strong adhesion and intracellular signaling.
• While its expression in normal adult tissues is largely restricted to basal layers (e.g., in the skin and mammary glands), CDH3 is frequently overexpressed in a variety of aggressive epithelial carcinomas, including breast (particularly triple-negative), gastric, ovarian, and pancreatic cancers. This aberrant overexpression is strongly correlated with poor prognosis, promoting tumorigenesis and metastasis through several key mechanisms:

1.  Enhanced Invasion and Metastasis: Contrary to its typical role as a suppressor of invasion, CDH3 overexpression in tumors can disrupt normal cellular organization. It promotes an aggressive, motile phenotype, often by inducing Epithelial-to-Mesenchymal Transition (EMT), a process crucial for cancer cell dissemination.

2.  Activation of Pro-Survival Signaling: The cytoplasmic engagement of β-catenin can lead to the stabilization and nuclear translocation of β-catenin, resulting in the transcriptional activation of oncogenic genes within the Wnt signaling pathway, thereby driving proliferation and inhibiting apoptosis.

3.  Maintenance of Cancer Stem Cell (CSC) Populations: CDH3 is a key marker and functional driver in subpopulations of CSCs. It helps maintain stemness, self-renewal, and resistance to therapy, contributing to tumor initiation, recurrence, and metastasis.

4.  Modulation of the Tumor Microenvironment: Through its adhesive functions, CDH3 facilitates interactions between tumor cells and the surrounding stroma, influencing pathways that support tumor growth, angiogenesis, and immune evasion.

• Due to its selective overexpression on cancer cells and its central role in driving malignancy, CDH3 has emerged as a promising therapeutic target for antibody-based therapies, including Antibody-Drug Conjugates (ADCs) and Bispecific Antibodies.
• In B-NDG hCDH3 mice, the exons 4-13 of mouse Cdh3 gene that encode the extracellular domain were replaced by human counterparts. A small amount of human CDH3 expression can be detected in the spleen, lung, kidney and brain of B-NDG hCDH3 mice, but a high level of human CDH3 expression can be detected in the skin of B-NDG hCDH3 mice.
• Application: This mouse model empowers the in vivo evaluation of CDH3-targeting therapeutic agents, such as antibodies, ADCs, and bispecifics, for efficacy and safety against human CDH3-expressing tumors.

Gene targeting strategy for B-NDG hCDH3 mice. The exons 4-13 of mouse Cdh3 gene that encode the extracellular domain is replaced by human counterparts in B-NDG hCDH3 mice. The genomic region of mouse Cdh3 gene that encodes the signal peptide, propeptide, transmembrane and cytoplasmic portion is retained. The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained. The chimeric CDH3 expression is driven by endogenous mouse Cdh3 promoter, while mouse Cdh3 gene transcription and translation will be disrupted.

Species specific analysis of CDH3 gene expression in wild-type B-NDG mice and homozygous B-NDG hCDH3 mice by RT-PCR. The skin tissues were collected from wild-type B-NDG mice (+/+) and homozygous B-NDG hCDH3 mice (H/H). Mouse Cdh3 mRNA was only detectable in wild-type B-NDG mice. Human CDH3 mRNA was only detectable in homozygous B-NDG hCDH3 mice, but not in wild-type B-NDG mice.

Strain specific CDH3 expression analysis in wild-type B-NDG mice (+/+) and homozygous humanized B-NDG hCDH3 mice (H/H) by western blot. The tissues of heart, spleen, lung, kidney, brain and skin were collected from wild-type B-NDG mice (+/+) and homozygous B-NDG hCDH3 mice (H/H) (female, 6-week-old, n=1). Protein expression was analyzed with anti-mouse CDH3 antibody (R&D, AF761-SP) and anti-human CDH3 antibody (R&D, MAB861-SP) by western blot. A small amount of mouse CDH3 expression can be detected in the spleen, lung and brain of wild-type B-NDG mice, but a high level of mouse CDH3 expression can be detected in the skin of B-NDG mice. A small amount of human CDH3 expression can be detected in the spleen, lung, kidney and brain of B-NDG hCDH3 mice, but a high level of human CDH3 expression can be detected in the skin of B-NDG hCDH3 mice.