Autophagy-dependent proteostasis suppresses breast cancer metastasis

Area of Science:

• Oncology
• Cell Biology
• Molecular Mechanisms of Cancer Metastasis

Background:

• Macroautophagy/autophagy normally suppresses breast cancer metastasis, but the underlying molecular mechanisms are not fully understood.
• Autophagy deficiency is linked to increased metastatic potential in breast cancer.
• Biomolecular condensate formation and its role in cancer progression are emerging areas of research.

Purpose of the Study:

• To elucidate the molecular mechanisms by which autophagy deficiency promotes breast cancer metastasis.
• To investigate the role of autophagy cargo receptors NBR1 and SQSTM1 in mediating metastatic potential.
• To identify potential therapeutic targets for preventing breast cancer metastasis in the context of autophagy deficiency.

Main Methods:

• Analysis of phase-separated biomolecular condensates in breast cancer cells with varying autophagy levels.
• Investigating the interaction between NBR1, SQSTM1, ITCH, and TP63.
• Assessing the impact of ITCH sequestration on TP63 stability and breast cancer cell differentiation state.

Main Results:

• Autophagy deficiency leads to the accumulation of NBR1-SQSTM1 biomolecular condensates.
• These condensates sequester the E3 ubiquitin ligase ITCH, preventing TP63 degradation.
• Stabilized and activated TP63 promotes an aggressive, basal-like differentiation state, enhancing metastatic potential.

Conclusions:

• NBR1-SQSTM1 condensates drive metastasis in autophagy-deficient breast cancer by stabilizing TP63.
• Defects in proteostasis due to autophagy impairment disrupt epithelial lineage fidelity and increase metastatic potential.
• Targeting NBR1-SQSTM1 condensates presents a potential therapeutic strategy to inhibit metastasis, particularly in autophagy-deficient cancers.