Naiara Santana-Codina1,2, Laia Muixí1, Ruben Foj1, Rebeca Sanz-Pamplona3,4, Miriam Badia-Villanueva5, Agata Abramowicz6, Anna Marcé-Grau1, Ana María Cosialls7, Joan Gil7, Ivan Archilla8, Leire Pedrosa9, Josep Gonzalez10, Iban Aldecoa8, Angels Sierra1,5,11. 1. Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 2. Autonomous University of Barcelona, Campus Bellaterra, Cerdanyola del Vallés, Barcelona, Spain. 3. Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 4. Centro de Investigación Biomédica en Red de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain. 5. Laboratory of Molecular and Translational Oncology, Center of Biomedical Research-August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 6. Maria Sklodowska-Curie Institute-Oncology Center, Gliwice, Poland. 7. Department of Physiological Sciences, School of Medicine and Health Sciences, Campus Bellvitge, Universitat de Barcelona, Oncobell, Bellvitge Medical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 8. Pathology Department, Center of Biomedical Diagnosis, Hospital Clínic, University of Barcelona, Barcelona, Spain. 9. Hematology and Oncology Department, Hospital Clinic Barcelona, IDIBAPS, Barcelona, Spain. 10. Department of Neurosurgery Hospital Clinic Barcelona, IDIBAPS Advances in Neurosurgery Research Group, Barcelona, Spain. 11. Health and Social Studies Center (CESS), University of Vic‒Central University of Catalonia, Vic, 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, 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.
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.
Authors: Isabell Witzel; Leticia Oliveira-Ferrer; Klaus Pantel; Volkmar Müller; Harriet Wikman Journal: Breast Cancer Res Date: 2016-01-19 Impact factor: 6.466
Authors: Edgar Petrosyan; Jawad Fares; Alex Cordero; Aida Rashidi; Víctor A Arrieta; Deepak Kanojia; Maciej S Lesniak Journal: Int J Cancer Date: 2022-03-04 Impact factor: 7.316