Wnt10b signaling regulates replication stress-induced chromosomal instability in human cancer

Abstract Wnt signaling pathways are involved in various developmental and tissue maintenance functions while deregulated Wnt signaling is closely linked to human cancer. Recent work revealed that loss of Wnt signaling impairs mitosis and causes abnormal microtubule growth at the mitotic spindle resulting in chromosome missegregation and aneuploidy, both of which are hallmarks of cancer cells exhibiting chromosomal instability (CIN). Here, we demonstrate that Wnt signaling specifically activated by Wnt10b is relevant in colorectal cancer cells to prevent abnormal microtubule dynamics and chromosome missegregation. Although mitosis is affected, Wnt10b signaling is required during the S phase of the cell cycle. In fact, Wnt10b signaling acts upon DNA replication stress in S phase, a condition typically associated with CIN in cancer, to prevent increased microtubule dynamics from S phase until mitosis, where they otherwise manifest in chromosome missegregation. Interestingly, replication stress-induced chromosomal breaks are also efficiently suppressed by Wnt10b. Thus, our results show that Wnt10b signaling regulates replication stress-induced chromosome missegregation and breakage, and hence, is a determinant for broad genome instability in cancer cells. Summary blurb We describe a novel role of Wnt10b signaling acting in response to DNA replication stress to suppress chromosomal breaks and mitotic errors in human cancer cells.