Autophagy-dependent proteostasis suppresses breast cancer metastasis.

In breast cancer, macroautophagy/autophagy suppresses key steps of the metastatic cascade, including colonization and outgrowth at distant sites. However, the molecular mechanisms behind this suppression have remained unclear. Our recent study shows that increased metastasis observed in the setting of autophagy deficiency is driven by the accumulation of phase-separated biomolecular condensates containing the autophagy cargo receptors NBR1 and SQSTM1. These NBR1-SQSTM1 condensates sequester ITCH, an E3 ubiquitin ligase responsible for degrading TP63, a transcription factor that promotes basal differentiation. Hence, ITCH sequestration stabilizes and activates TP63 in breast cancer cells, hence promoting an aggressive, pro-metastatic basal-like differentiation state. Overall, our findings suggest that the potential benefits of targeting autophagy in cancer therapy are accompanied by defects in proteostasis, which disrupts epithelial lineage fidelity and enhances metastatic potential. We propose that targeting NBR1-SQSTM1 condensates may offer new therapeutic avenues to prevent metastasis, particularly in the context of autophagy deficiency.