A schematic representation of NOTCH signaling through DAB1–ABL–TRIO–RHO that stimulates colorectal cancer invasion and metastasis. A schematic representation of NOTCH signaling through DAB1–ABL–TRIO–RHO that stimulates colorectal cancer invasion and metastasis. Stromal cells, including endothelial cells (EC), can activate NOTCH signaling in colorectal cancer cells and upregulate DAB1 transcription, activating ABL when the AES level is low. Activated by DAB1, ABL enhances the RHOGEF activity of TRIO by phosphorylating Y2681. Thus, TRIO pY2681 is critical for the RHO activation that contributes to invasion, intra- and extravasation, and metastasis of colorectal cancer cells. In addition, a possibility remains that other products of RBPJ transcription as well as other tyrosine kinases may also be involved in colorectal cancer invasion and metastasis. These results provide a possible prognostic marker in TRIO pY2681 and a therapeutic strategy targeting ABL (e.g., using imatinib and related drugs) to prevent colorectal cancer metastasis. Masahiro Sonoshita et al. Cancer Discovery 2015;5:198-211 ©2015 by American Association for Cancer Research