Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression.
Keratin14
NBR1
Rubicon
TP63
autophagy
breast cancer
chloroquine
metastasis
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
09 03 2020
09 03 2020
Historique:
received:
22
06
2019
revised:
25
11
2019
accepted:
22
01
2020
pubmed:
23
2
2020
medline:
23
10
2020
entrez:
22
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32084360
pii: S1534-5807(20)30057-5
doi: 10.1016/j.devcel.2020.01.025
pmc: PMC7108946
mid: NIHMS1569021
pii:
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Nbr1 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
591-604.e6Subventions
Organisme : NCI NIH HHS
ID : R21 CA201849
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063720
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA167905
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA126792
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188404
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213775
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA217015
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA108462
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA057621
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests J.D. is a scientific advisory board member for Vescor Therapeutics, LLC. Z.W. is a scientific advisory board member for Maverick Therapeutics, Inc.
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