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Simple Summary: Vessel co-option has been recognized as a mechanism associated with resistance to anti-angiogenic treatment in colorectal cancer liver metastases (CRCLMs). Recently, we reported that Angiopoietin-1 (Ang1) stimulates vessel co-option in CRCLM through an unknown mechanism. In this manuscript, we found the molecular pathways that mediate the function of Ang1 in CRCLM. We showed that Ang1 induces the expression levels of actin-related protein 2/3 (ARP2/3) in the cancer cells via various mechanisms. Importantly, different studies have shown that high levels of ARP2/3 in cancer cells are essential for the formation of vessel co-opting CRCLM tumours. Highlighting these pathways is an important step to identify therapeutic strategies to overcome vessel co-option and resistance to anti-angiogenic therapy in CRCLM. Resistance to anti-angiogenic therapy is a major challenge in the treatment of colorectal cancer liver metastases (CRCLMs). Vessel co-option has been identified as a key contributor to anti-angiogenic therapy resistance in CRCLMs. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) in the liver and the development of vessel co-opting CRCLM lesions in vivo. However, the mechanisms underlying its stimulation of vessel co-option are unclear. Herein, we demonstrated Ang1 as a positive regulator of actin-related protein 2/3 (ARP2/3) expression in cancer cells, in vitro and in vivo, which is known to be essential for the formation of vessel co-option in CRCLM. Significantly, Ang1-dependent ARP2/3 expression was impaired in the cancer cells upon Tie2 or PI3K/AKT inhibition in vitro. Taken together, our results suggest novel mechanisms by which Ang1 confers the development of vessel co-option in CRCLM, which, targeting this pathway, may serve as promising therapeutic targets to overcome the development of vessel co-option in CRCLM. [ABSTRACT FROM AUTHOR]