Classification of prostate cancer using a protease activity nanosensor library
Classification of prostate cancer using a protease activity nanosensor library
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DOI：
10.1073/pnas.1805337115
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发表时间：
2018-09-04
影响因子：
11.1
通讯作者：
Bhatia, Sangeeta N.
中科院分区：
文献类型：
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作者：
Dudani, Jaideep S.;Ibrahim, Maria;Bhatia, Sangeeta N.
前列腺癌需要改进的生物标志物，因为目前的金标准预测价值很差。循环前列腺特异性抗原（PSA）水平的测试易受前列腺中各种非癌症合并症的影响，并且不能提供预后信息，而物理活检是侵入性的，必须重复进行，并且仅对前列腺的一部分进行采样。可注射生物传感器可以通过非侵入性读出来查询前列腺的状态，从而为前列腺癌生物标志物提供新的范例。蛋白酶是一类重要的酶，在癌症的每一个标志中发挥作用;它们的活性可以作为生物标志物。我们通过转录组学和蛋白质组学分析鉴定了一组前列腺癌蛋白酶。使用这个面板，我们开发了一个纳米传感器库，该库使用荧光在体外测量蛋白酶活性，并使用尿液读数在体内测量蛋白酶活性。在异种移植小鼠模型中，我们应用该纳米传感器库对侵袭性前列腺癌进行分类并选择预测底物。最后，我们共同制定了一个子集的纳米传感器与整合素靶向配体，以提高灵敏度。这些靶向纳米传感器有力地分类了前列腺癌的侵袭性，并优于PSA。这种基于活性的纳米传感器库在前列腺癌的临床管理中可能是有用的，具有诊断和预后效用。
Improved biomarkers are needed for prostate cancer, as the current gold standards have poor predictive value. Tests for circulating prostate-specific antigen (PSA) levels are susceptible to various noncancer comorbidities in the prostate and do not provide prognostic information, whereas physical biopsies are invasive, must be performed repeatedly, and only sample a fraction of the prostate. Injectable biosensors may provide a new paradigm for prostate cancer biomarkers by querying the status of the prostate via a noninvasive readout. Proteases are an important class of enzymes that play a role in every hallmark of cancer; their activities could be leveraged as biomarkers. We identified a panel of prostate cancer proteases through transcriptomic and proteomic analysis. Using this panel, we developed a nanosensor library that measures protease activity in vitro using fluorescence and in vivo using urinary readouts. In xenograft mouse models, we applied this nanosensor library to classify aggressive prostate cancer and to select predictive substrates. Last, we coformulated a subset of nanosensors with integrin-targeting ligands to increase sensitivity. These targeted nanosensors robustly classified prostate cancer aggressiveness and outperformed PSA. This activity-based nanosensor library could be useful throughout clinical management of prostate cancer, with both diagnostic and prognostic utility.