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

Abstract

AbstractColorectal 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 [1]. 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 XAV-939 or ICG-001 partially prevented centrinone-induced death and rescued the growth of APC-mutant organoid lines. Our study reveals a novel role for canonical WNT signaling in regulating centrosome loss-induced growth defect/death in APC-mutant colorectal cancer independently of the classical p53 pathway.