GRP94 promotes brain metastasis by engaging pro-survival autophagy.
Neuro Oncol
; 22(5): 652-664, 2020 05 15.
Article
em En
| MEDLINE
| ID: mdl-31637425
ABSTRACT
BACKGROUND:
GRP94 is a glucose-regulated protein critical for survival in endoplasmic reticulum stress. Expression of GRP94 is associated with cellular transformation and increased tumorigenicity in breast cancer. Specifically, overexpression of GRP94 predicts brain metastasis (BM) in breast carcinoma patients with either triple negative or ErbB2 positive tumors. The aim of this study was to understand if microenvironmental regulation of GRP94 expression might be a hinge orchestrating BM progression.METHODS:
GRP94 ablation was performed in a BM model BR-eGFP-CMV/Luc-V5CA1 (BRV5CA1) of breast cancer. In vitro results were validated in a dataset of 29 metastases in diverse organs from human breast carcinomas and in BM tissue from tumors of different primary origin. BM patient-derived xenografts (PDXs) were used to test sensitivity to the therapeutic approach.RESULTS:
BMs that overexpress GRP94 as well as tumor necrosis factor receptor-associated factor 2 are more resistant to glucose deprivation by induction of anti-apoptotic proteins (B-cell lymphoma 2 and inhibitors of apoptosis proteins) and engagement of pro-survival autophagy. GRP94 ablation downregulated autophagy in tumor cells, resulting in increased BM survival in vivo. These results were validated in a metastasis dataset from human patients, suggesting that targeting autophagy might be strategic for BM prevention. Indeed, hydroxychloroquine treatment of preclinical models of BM from PDX exerts preventive inhibition of tumor growth (P < 0.001).CONCLUSIONS:
We show that GRP94 is directly implicated in BM establishment by activating pro-survival autophagy. Disruption of this compensatory fueling route might prevent metastatic growth.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Encefálicas
/
Proteínas de Membrana
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Neuro Oncol
Assunto da revista:
NEOPLASIAS
/
NEUROLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Espanha