Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California, USA.
Wyant College of Optical Sciences, University of Arizona, Tucson, Arizona, USA.
Mol Cell Proteomics. 2023 Jul;22(7):100590. doi: 10.1016/j.mcpro.2023.100590. Epub 2023 Jun 9.
Ovarian cancer, a leading cause of cancer-related deaths among women, has been notoriously difficult to screen for and diagnose early, as early detection significantly improves survival. Researchers and clinicians seek routinely usable and noninvasive screening methods; however, available methods (i.e., biomarker screening) lack desirable sensitivity/specificity. The most fatal form, high-grade serous ovarian cancer, often originate in the fallopian tube; therefore, sampling from the vaginal environment provides more proximal sources for tumor detection. To address these shortcomings and leverage proximal sampling, we developed an untargeted mass spectrometry microprotein profiling method and identified cystatin A, which was validated in an animal model. To overcome the limits of detection inherent to mass spectrometry, we demonstrated that cystatin A is present at 100 pM concentrations using a label-free microtoroid resonator and translated our workflow to patient-derived clinical samples, highlighting the potential utility of early stage detection where biomarker levels would be low.
卵巢癌是导致女性癌症相关死亡的主要原因，其早期筛查和诊断一直难以实现，因为早期发现显著提高了生存率。研究人员和临床医生正在寻找常规可用且非侵入性的筛查方法；然而，现有的方法（即生物标志物筛查）缺乏理想的灵敏度/特异性。最致命的形式，高级别浆液性卵巢癌，通常起源于输卵管；因此，从阴道环境中取样为肿瘤检测提供了更接近的来源。为了解决这些缺点并利用近距离采样，我们开发了一种非靶向的质谱微蛋白分析方法，并鉴定出半胱氨酸蛋白酶抑制剂 A，该方法在动物模型中得到了验证。为了克服质谱固有的检测极限，我们证明了半胱氨酸蛋白酶抑制剂 A 以 100 pM 的浓度存在，使用无标记的微环形谐振器，并将我们的工作流程转化为患者衍生的临床样本，突出了在生物标志物水平较低的早期检测中的潜在应用。
