The Expression and Molecular Roles of MAMDC2 in MSS Colorectal Cancer with a High Tumor Stromal Ratio

<b>Background:</b> Colorectal cancer (CRC) heterogeneity is strongly influenced by molecular subtypes and tumor stroma interactions. The meprin/A5/PTPmu (MAM) domain, a conserved structural motif in transmembrane proteins, remains undercharacterized in CRC pathogenesis. <b>Methods:</b> We analyzed RNA-seq data from TCGA-COAD to evaluate MAM domain gene expression. Immunohistochemistry and Western blotting were conducted to validate the results of the database analysis. <b>Results:</b> Bioinformatics analysis revealed that MAM domain-containing protein 2 (MAMDC2) was enriched in mesenchymal subtype 4 (CMS4) colorectal cancer (<i>p</i> < 0.001). IHC confirmed MAMDC2 overexpression in MSS colorectal cancer with a high tumor stroma ratio (TSR) and peritoneal metastatic lesions (<i>p</i> < 0.01). WB and real-time PCR analyses confirmed that MAMDC2 has a role in regulating epithelial-mesenchymal transition (EMT) development in CRC. Importantly, we identified that cancer cell-derived MAMDC2 promotes MYLK expression in cancer-associated fibroblasts (CAFs) through paracrine signaling. <b>Conclusions:</b> Our findings suggest MAMDC2 may function as a stromal-associated regulator in MSS colorectal cancer with a high tumor stromal ratio (TSR).