Global secretome analysis identifies novel mediators of bone metastasis.
Bone is the one of the most common sites of distant metastasis of solid tumors. Secreted proteins are known to influence pathological interactions between metastatic cancer cells and the bone stroma. To comprehensively profile secreted proteins associated with bone metastasis, we used quantitative and non-quantitative mass spectrometry to globally analyze the secretomes of nine cell lines of varying bone metastatic ability from multiple species and cancer types. By comparing the secretomes of parental cells and their bone metastatic derivatives, we identified the secreted proteins that were uniquely associated with bone metastasis in these cell lines. We then incorporated bioinformatic analyses of large clinical metastasis datasets to obtain a list of candidate novel bone metastasis proteins of several functional classes that were strongly associated with both clinical and experimental bone metastasis. Functional validation of selected proteins indicated that in vivo bone metastasis can be promoted by high expression of (1) the salivary cystatins CST1, CST2, and CST4; (2) the plasminogen activators PLAT and PLAU; or (3) the collagen functionality proteins PLOD2 and COL6A1. Overall, our study has uncovered several new secreted mediators of bone metastasis and therefore demonstrated that secretome analysis is a powerful method for identification of novel biomarkers and candidate therapeutic targets.
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Mario Andres
MA
Blanco
Gary
G
LeRoy
Zia
Z
Khan
Maša
M
Alečković
Barry M
BM
Zee
Benjamin A
BA
Garcia
Yibin
Y
Kang
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D024142:Collagen Type VI / Q000378:metabolism; D019295:Computational Biology; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D009369:Neoplasms / Q000473:pathology; D010960:Plasminogen Activators / Q000378:metabolism; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D040901:Proteomics; D055333:Salivary Cystatins / Q000378:metabolism
D014408:Biomarkers, Tumor; C525171:CST1 protein, human; C525172:CST2 protein, human; C525173:CST4 protein, human; C553839:Col6a1 protein, human; D024142:Collagen Type VI; D020543:Proteome; D055333:Salivary Cystatins; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D010960:Plasminogen Activators