Colonic stem cells maintain a delicate balance with their surrounding microenvironment. This homeostasis is increasingly disturbed during colon cancer progression, which perpetuates the expansion and invasion of cancerous tissue. To decipher the interactions between colonic stem cells or tumor cells and their microenvironment, researchers examined Wnt signaling in cancer cell lines and patient-derived organoids. Wnt signaling is a major driver of stemness in epithelial cells in the colon and of colorectal cancer. Findings revealed that Wnt activity triggered the expression of the gene LARGE2, which in turn mediates the laminin-adhesive O-glycosylation of α-DG. The result was abnormally increased cellular adhesion to laminin during Wnt-driven cancer progression. While in vivo studies are needed to understand the disease relevance of this Wnt/LARGE2/α-DG axis, the observations could help researchers better understand colorectal cancer invasion and metastasis.