Herein, using a series of in vitro, animal studies and clinical patient cohorts, we for the first time report that TIAM1 is a key Wnt-signaling gene that is frequently overexpressed in CRC, which leads to enhanced drug resistance and stemness in CRC, and a process that is tightly orchestrated by the CAFs within the tumor microenvironment in CRC. The gene discussed is TIAM1; the disease is colorectal carcinoma.