CDH22 (cadherin 22) is a calcium-dependent cell adhesion protein that functions in cell-cell adhesion through homophilic interactions 1. It is highly expressed in the pituitary gland and brain, where it contributes to morphological organization of neural and neuroendocrine tissues 2. CDH22 localizes to adherens junctions and interacts with beta-catenin and other catenin complex components to mediate cell-cell junction assembly and cell migration 2. In colorectal cancer, CDH22 is significantly over-expressed at transcriptional and translational levels compared to normal mucosa, and its over-expression correlates with invasion, metastasis, and lymphatic spread 2. CDH22 knockdown attenuates cancer cell proliferation and invasion in vitro and inhibits tumor metastasis in vivo 2. Mechanistically, CDH22 interacts directly with PRL-3, a metastasis-associated protein, and PRL-3 promotes CDH22 downregulation during epithelial-mesenchymal transition 3. In breast cancer, CDH22 is hypermethylated in promoter CpG sites, and this epigenetic silencing is an independent predictor of poor progression-free and overall survival 1. Additionally, CDH22 harbors sex-specific genetic variants (rs2425786, rs2425788) associated with myeloproliferative neoplasm phenotypes 4. These findings establish CDH22 as a context-dependent regulator of cancer progression with potential clinical significance as a biomarker and therapeutic target.