Centrosome amplification in cancer disrupts autophagy and sensitizes to autophagy inhibition

Abstract

Centrosome amplification (CA), or a numerical increase in centrosomes, is common in human cancers, particularly those with high-risk features. We have discovered that cells with CA have an increased burden of autophagy, a catabolic process whereby autophagosomes engulf damaged organelles and proteins and deliver these contents to the lysosome for degradation and subsequent recycling. Cells with CA demonstrate an accumulation of autophagosomes. We evaluated the alternative hypotheses that CA alters autophagy by modulating microtubule networks and impairing trafficking versus altering lysosome clustering and organization versus chromosome missegregation-induced proteotoxic stress. Using LC3 reporter assays and autophagosome tracking experiments, we demonstrate that CA causes an accumulation of autophagosomes by interfering with autophagosome trafficking. To establish whether this was a druggable weakness, we tested autophagy inhibitors in our cell models of CA. Cells withCAare sensitized to chemical and genetic autophagy inhibition. Taken together, our results suggest that autophagy is disrupted byCAand sensitizes cells to inhibition of autophagy. These findings suggest a novel precision medicine strategy, whereby CA increases reliance on autophagy and serves as a biomarker for autophagy inhibitors in high-risk cancers.