Alečković Maša, Wei Yong, LeRoy Gary, Sidoli Simone, Liu Daniel D, Garcia Benjamin A, Kang Yibin
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genes Dev. 2017 Jul 15;31(14):1439-1455. doi: 10.1101/gad.301937.117. Epub 2017 Aug 21.
Secreted proteins play crucial roles in mediating tumor-stroma interactions during metastasis of cancer to different target organs. To comprehensively profile secreted proteins involved in lung metastasis, we applied quantitative mass spectrometry-based proteomics and identified 392 breast cancer-derived and 302 melanoma-derived proteins secreted from highly lung metastatic cells. The cancer-specific lung metastasis secretome signatures (LMSSs) displayed significant prognostic value in multiple cancer clinical data sets. Moreover, we observed a significant overlap of enriched pathways between the LMSSs of breast cancer and melanoma despite an overall small overlap of specific proteins, suggesting that common biological processes are executed by different proteins to enable the two cancer types to metastasize to the lung. Among the novel candidate lung metastasis proteins, Nidogen 1 (NID1) was confirmed to promote lung metastasis of breast cancer and melanoma, and its expression is correlated with poor clinical outcomes. In vitro functional analysis further revealed multiple prometastatic functions of NID1, including enhancing cancer cell migration and invasion, promoting adhesion to the endothelium and disrupting its integrity, and improving vascular tube formation capacity. As a secreted prometastatic protein, NID1 may be developed as a new biomarker for disease progression and therapeutic target in breast cancer and melanoma.
分泌蛋白在癌症转移至不同靶器官的过程中，介导肿瘤与基质相互作用方面发挥着关键作用。为全面剖析参与肺转移的分泌蛋白，我们应用基于定量质谱的蛋白质组学技术，鉴定出从高肺转移细胞分泌的392种乳腺癌源蛋白和302种黑色素瘤源蛋白。癌症特异性肺转移分泌组特征（LMSSs）在多个癌症临床数据集中显示出显著的预后价值。此外，尽管特定蛋白的总体重叠较小，但我们观察到乳腺癌和黑色素瘤的LMSSs之间富集途径存在显著重叠，这表明不同蛋白执行共同的生物学过程，以使这两种癌症类型能够转移至肺部。在新的候选肺转移蛋白中，巢蛋白1（NID1）被证实可促进乳腺癌和黑色素瘤的肺转移，其表达与不良临床结局相关。体外功能分析进一步揭示了NID1的多种促转移功能，包括增强癌细胞迁移和侵袭、促进与内皮细胞的黏附并破坏其完整性，以及提高血管管形成能力。作为一种分泌型促转移蛋白，NID1有望开发成为乳腺癌和黑色素瘤疾病进展的新生物标志物及治疗靶点。
