Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression

• Published in: Developmental cell Vol. 52; no. 5; pp. 591 - 604.e6
• Main Authors: Marsh, Timothy, Kenific, Candia M., Suresh, Deepthisri, Gonzalez, Hugo, Shamir, Eliah R., Mei, Wenbin, Tankka, Alexandra, Leidal, Andrew M., Kalavacherla, Sandhya, Woo, Kimberly, Werb, Zena, Debnath, Jayanta
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-03-2020
• Subjects: Animals; Autophagy; breast cancer; Cells, Cultured; chloroquine; Female; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Keratin14; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; MCF-7 Cells; metastasis; Mice; Mice, Inbred C57BL; NBR1; Neoplasm Metastasis; Rubicon; TP63; Transcriptome; Keratin14; chloroquine; autophagy; Rubicon; metastasis; NBR1; breast cancer; TP63
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.01.025

Although autophagy is being pursued as a therapeutic target in clinical oncology trials, its effects on metastasis, the principal cause of cancer mortality, remain unclear. Here, we utilize mammary cancer models to temporally delete essential autophagy regulators during carcinoma progression. Though genetic ablation of autophagy strongly attenuates primary mammary tumor growth, impaired autophagy promotes spontaneous metastasis and enables the outgrowth of disseminated tumor cells into overt macro-metastases. Transcriptomic analysis reveals that autophagy deficiency elicits a subpopulation of otherwise luminal tumor cells exhibiting basal differentiation traits, which is reversed upon preventing accumulation of the autophagy cargo receptor, Neighbor to BRCA1 (NBR1). Furthermore, pharmacological and genetic induction of autophagy suppresses pro-metastatic differentiation and metastatic outgrowth. Analysis of human breast cancer data reveal that autophagy gene expression inversely correlates with pro-metastatic differentiation signatures and predicts overall and distant metastasis-free survival. Overall, these findings highlight autophagy-dependent control of NBR1 as a key determinant of metastatic progression.
[Display omitted]
•Autophagy promotes primary tumor growth, yet suppresses metastatic outgrowth•Autophagy deficiency elicits a pro-metastatic basal tumor cell subpopulation•NBR1 accumulation mediates the effects of autophagy inhibition on metastasis•Enforced autophagy induction prevents the outgrowth of disseminated tumor cells
Autophagy is a therapeutic target in cancer, but its role during metastasis remains incompletely understood. In mammary cancer models, Marsh et al. demonstrate that autophagic degradation of NBR1 suppresses metastatic outgrowth by restricting an aggressive, basal subpopulation of tumor cells. Enforced autophagy is a potential therapeutic approach to prevent metastases.