β-catenin mediates growth defects induced by centrosome loss in a subset of APC mutant colorectal cancer independently of p53

Colorectal Cancer is the third most common Cancer and the second leading cause of cancer-related deaths worldwide. The centrosome is the main microtubule-organizing center in animal cells and centrosome amplification is a hallmark of Cancer cells. To investigate the importance of centrosomes in colorectal Cancer, we induced centrosome loss in normal and Cancer human-derived colorectal organoids using centrinone B, a Polo-like kinase 4 (PLK4) inhibitor. We show that centrosome loss represses human normal colorectal organoid growth in a p53-dependent manner in accordance with previous studies in cell models. However, Cancer colorectal organoid lines exhibited different sensitivities to centrosome loss independently of p53. Centrinone-induced Cancer organoid growth defect/death positively correlated with a loss of function mutation in the APC gene, suggesting a causal role of the hyperactive Wnt pathway. Consistent with this notion, β-catenin inhibition using XAV939 or ICG-001 partially prevented centrinone-induced death and rescued the growth two APC-mutant organoid lines tested. Our study reveals a novel role for canonical Wnt signaling in regulating centrosome loss-induced growth defect/death in a subset of APC-mutant colorectal Cancer independently of the classical p53 pathway.