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 experi-ments, 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 with CA are sensitized to chemical and genetic autophagy inhibition. Taken together, our results suggest that autophagy is disrupted by CA and 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.Implications: Our study suggests that CA could be used as a predictive biomarker for treatment with autophagy inhibitors.

Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption

“… 53 Centrosome amplification was recently shown to disrupt autophagy, rendering these cells sensitive to autophagy inhibitors. 54 We currently do not know whether lysosome dysfunction is responsible for the autophagy defects observed in these cells. However, it is reasonable to assume that ROS-mediated lysosomal dysregulation could have a broader impact on the physiology of cells carrying centrosomal abnormalities.…”

Endoplasmic reticulum acetyltransferases Atase1 and Atase2 differentially regulate reticulophagy, macroautophagy and cellular acetyl-CoA metabolism

“…MEFs were nucleofected with pGFP-LC3, a gift from Tamotsu Yoshimori (Addgene #21073) 53 , and plated on a glass bottom 35 mm dishes (MatTek; #P35G-1.5-14-C) or plated and transduced with BacMam LC3β-GFP as described above. After 20–24 h, cells were imaged live using the Andor Revolution XD spinning disc microscopy system as previously described 54 .…”

Centrosome amplification mediates small extracellular vesicles secretion via lysosome disruption

“…Fusion of lysosomes with autophagosomes is critical during autophagy, a self-degradative process important for the removal of protein aggregates, damaged organelles and intracellular pathogens [49]. Interestingly, centrosome amplification was recently shown to disrupt autophagy, rendering these cells sensitive to autophagy inhibitors [50]. Whether lysosome dysfunction is responsible for the autophagy defects observed in these cells is currently unknown.…”