Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression.

Abstract:

: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.

journal_name

Dev Cell

journal_title

Developmental cell

authors

Marsh T,Kenific CM,Suresh D,Gonzalez H,Shamir ER,Mei W,Tankka A,Leidal AM,Kalavacherla S,Woo K,Werb Z,Debnath J

doi

10.1016/j.devcel.2020.01.025

subject

Has Abstract

pub_date

2020-03-09 00:00:00

pages

591-604.e6

issue

5

eissn

1534-5807

issn

1878-1551

pii

S1534-5807(20)30057-5

journal_volume

52

pub_type

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