Lung adenocarcinoma (LUAD) is the second most common cancer, affecting both men and women. Fibrosis is a hallmark of LUAD occurring throughout progression with excess production of extracellular matrix (ECM) components that lead to metastatic cell processes. Understanding the ECM cues that drive LUAD progression has been limited due to a lack of tools that can access and report on ECM components within the complex tumor microenvironment. Here, we test whether low-grade LUAD can be distinguished from normal lung tissue using a novel ECM imaging mass spectrometry (ECM IMS) approach. ECM IMS analysis of a tissue microarray with 20 low-grade LUAD tissues and 20 normal lung samples from 10 patients revealed 25 peptides that could discriminate between normal and low-grade LUAD using area under the receiver-operating curve (AUC) ≥0.7, P value ≤.001. Principal component analysis demonstrated that 62.4% of the variance could be explained by sample origin from normal or low-grade tumor tissue. Additional work performed on a wedge resection with moderately differentiated LUAD demonstrated that the ECM IMS analytical approach could distinguish LUAD spectral features from spectral features of normal adjacent lung tissue. Conventional liquid chromatography with tandem mass spectrometry (LC-MS/MS) proteomics demonstrated that specific sites of hydroxylation of proline (HYP) were a main collagen post translational modification that was readily detected in LUAD. A distinct peptide from collagen 3A1 modified by HYP was increased 3.5 fold in low-grade LUAD compared with normal lung tissue (AUC 0.914, P value <.001). This suggests that regulation of collagen proline hydroxylation could be an important process during early LUAD fibrotic deposition. ECM IMS is a useful tool that may be used to define fibrotic deposition in low-grade LUAD.

中文翻译：

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通过成像质谱法比较低级别肺腺癌与正常肺组织的细胞外基质变化。


肺腺癌 (LUAD) 是第二常见的癌症，影响男性和女性。纤维化是 LUAD 的一个标志，在整个进展过程中都会发生，细胞外基质 (ECM) 成分的过量产生会导致细胞转移过程。由于缺乏能够访问和报告复杂肿瘤微环境中 ECM 成分的工具，对驱动 LUAD 进展的 ECM 线索的理解受到限制。在这里，我们使用新型 ECM 成像质谱 (ECM IMS) 方法测试是否可以将低级别 LUAD 与正常肺组织区分开。对包含 20 个低级别 LUAD 组织和来自 10 名患者的 20 个正常肺样本的组织微阵列进行 ECM IMS 分析，发现有 25 种肽可以使用受试者工作曲线下面积 (AUC) ≥0.7 来区分正常和低级别 LUAD，P值≤.001。主成分分析表明，62.4% 的方差可以用正常或低级别肿瘤组织的样本来源来解释。对具有中等分化 LUAD 的楔形切除进行的其他工作表明，ECM IMS 分析方法可以区分 LUAD 光谱特征和正常相邻肺组织的光谱特征。传统液相色谱与串联质谱 (LC-MS/MS) 蛋白质组学证明，脯氨酸羟基化 (HYP) 的特定位点是主要的胶原蛋白翻译后修饰，在 LUAD 中很容易检测到。与正常肺组织相比，经 HYP 修饰的来自胶原蛋白 3A1 的独特肽在低级别 LUAD 中增加了 3.5 倍（AUC 0.914，P 值 <.001）。这表明胶原脯氨酸羟基化的调节可能是早期 LUAD 纤维化沉积过程中的一个重要过程。 ECM IMS 是一种有用的工具，可用于定义低级别 LUAD 中的纤维化沉积。