FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies.
Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83-9.71) and 2.55- (95%CI 1.52-4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.
Biological Clues of The Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Spain.|Universitat Autònoma de Barcelona (UAB), Biochemistry and Molecular Biology Department, Faculty of Biosciences, Campus Bellaterra, Edifici C, Cerdanyola del Vallés, 08193 Barcelona, Spain.
Antonio
A
Martínez-Aranda
Biological Clues of The Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Vanessa
V
Hernández
Structural Bioinformatics Laboratory, Experimental Sciences Department, Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine, 08003 Barcelona, Spain.
Emre
E
Guney
Biological Clues of The Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Laia
L
Muixí
Biological Clues of The Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Spain.|Universitat Autònoma de Barcelona (UAB), Biochemistry and Molecular Biology Department, Faculty of Biosciences, Campus Bellaterra, Edifici C, Cerdanyola del Vallés, 08193 Barcelona, Spain.
Ruben
R
Foj
Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Núria
N
Baixeras
Biomarkers and Susceptibility Unit, Institut Català d'Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Daniel
D
Cuadras
Biomarkers and Susceptibility Unit, Institut Català d'Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Víctor
V
Moreno
Breast Cancer Unit and Neuroncology Unit, Institut Català d'Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Ander
A
Urruticoechea
Oncology Service, Institut Català d'Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Miguel
M
Gil
Structural Bioinformatics Laboratory, Experimental Sciences Department, Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine, 08003 Barcelona, Spain.
Baldo
B
Oliva
Radiation Oncology Service, Institut Català d'Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Ferran
F
Moreno
Transformation and Metastasis Group, Cancer Epigenetics and Biology Department, IDIBELL, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Eva
E
González-Suarez
Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Noemí
N
Vidal
Pathology Service, Corporació Sanitaria Parc Taulí, 08208 Sabadell, Spain.
Xavier
X
Andreu
Oncology Service, Corporació Sanitaria Parc Taulí, 08208 Sabadell, Spain.
Miquel A
MA
Seguí
Radiation Oncology Service, Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.
Rosa
R
Ballester
Pathology Service, Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.
Eva
E
Castella
Biological Clues of The Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Spain.|Molecular and Translational Oncology Laboratory, Biomedical Research Center CELLEX-CRBC Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS 08036 Barcelona, Spain.
Angels
A
Sierra
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D019540:Area Under Curve; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D045744:Cell Line, Tumor; D000074049:Cytokine TWEAK; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016013:Likelihood Functions; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D008875:Middle Aged; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D012307:Risk Factors; D013030:Spain; D000074050:TWEAK Receptor; D013792:Thalidomide / Q000627:therapeutic use; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment; D048069:Tumor Necrosis Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D000074049:Cytokine TWEAK; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors; C053387:endoplasmin; D013792:Thalidomide
FN14; GRP94; biomarkers; brain metastasis; breast cancer