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Neuro Oncol. 2019 Oct 22. pii: noz198. doi: 10.1093/neuonc/noz198. [Epub ahead of print]

GRP94 promotes brain metastasis by engaging pro-survival autophagy.

Author information

1
Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
2
Universitat Autònoma de Barcelona (UAB), Campus Bellaterra, Cerdanyola del Vallés, Barcelona, Spain.
3
Unit of Biomarkers and Susceptibility, ICO-IDIBELL and CIBERESP, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
4
Laboratory of Molecular and Translational Oncology, Centre de Recerca Biomèdica CELLEX-CRBC- Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Barcelona, Spain.
5
Maria Sklodowska-Curie Institute-Oncology Centre (MSCI), Gliwice, Poland.
6
Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
7
Pathology Department Center of Biomedical Diagnosis (CDB), Hospital Clínic, University of Barcelona, Barcelona, Spain.
8
Haemathology and Oncology Department, Hospital Clinic Barcelona. IDIBAPS, Barcelona, Spain.
9
Department of Neurosurgery Hospital Clinic Barcelona. IDIBAPS Advances in Neurosurgery Research Group. Barcelona, Spain.
10
Centre d'Estudis Sanitaris i Socials-CESS. University of Vic - Central University of Catalonia (UVic-UCC), Spain.

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, over-expression of GRP94 predicts brain metastasis 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 brain metastasis (BrM) progression.

METHODS:

GRP94 ablation was performed in a BrM model BR-eGFP-CMV/Luc-V5CA1 (BRV5CA1) of breast cancer. In vitro results were validated in a data set of 29 metastases in diverse organs from human breast carcinomas and in BrM tissue from tumors of different primary origin. BrM patient-derived xenografts (PDX) were used to test sensitivity to the therapeutic approach.

RESULTS:

BrM that over-express GRP94 as well as TRAF2 are more resistant to glucose deprivation by induction of anti-apoptotic proteins (BCL2 and IAPs) and engagement of pro-survival autophagy. GRP94 ablation down-regulated autophagy in tumor cells, resulting in decreased survival in vivo. These results were validated in a metastasis data set from human patients suggesting that targeting autophagy might be strategic for BrM prevention. Indeed, hydroxychloroquine treatment of preclinical models of BrM from PDX exerts preventive inhibition of tumor growth (p<0,001).

CONCLUSIONS:

We show that GRP94 is directly implicated in BrM establishment by activating pro-survival autophagy. Disruption of this compensatory fueling route might prevent metastatic growth.

KEYWORDS:

Autophagy; Biomarker; Brain metastasis; Breast cancer; Endoplasmic Reticulum stress; GRP94

PMID:
31637425
DOI:
10.1093/neuonc/noz198

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