De novo discovery of phenotypic intratumour heterogeneity using imaging mass spectrometry
De novo discovery of phenotypic intratumour heterogeneity using imaging mass spectrometry
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DOI：
10.1002/path.4436
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发表时间：
2015-01-01
影响因子：
7.3
通讯作者：
McDonnell, Liam A.
中科院分区：
文献类型：
--
作者：
Balluff, Benjamin;Frese, Christian K.;McDonnell, Liam A.
肿瘤内克隆性和表型的异质性是影响肿瘤演变和患者临床治疗的一个重要且迄今尚未解决的因素。然而，到目前为止，肿瘤亚群的从头识别既是一项具有挑战性的任务，也是一项尚未解决的任务。在这里，我们提出了第一个系统的方法，从头发现临床有害的分子肿瘤亚群。在这项原理验证研究中，使用基质辅助激光解吸/电离(MALDI)成像质谱仪，从63例胃癌和32例乳腺癌患者的组织中获得了空间分辨的肿瘤特异性质谱图。代表肿瘤区域内蛋白质组异质性的质谱图被确证的统计聚类算法分组，以获得分子上不同区域的分割图。推测这些区域代表不同的表型肿瘤亚群。通过将这些肿瘤亚群的存在与患者的临床数据联系起来，证实了这一点。这表明，检测到的几个肿瘤亚群与胃癌患者的总体存活率(p=0.025)和乳腺癌患者局部区域转移的存在(p=0.036)有关。提出的程序是通用的，并在癌症研究中开辟了新的选择，因为它揭示了显微镜下模糊的肿瘤亚群对临床结果有不利影响。这使得他们能够进一步进行分子表征，以更深入地了解癌症的生物过程，这可能最终导致新的靶向治疗。版权所有(C)2014年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
An essential and so far unresolved factor influencing the evolution of cancer and the clinical management of patients is intratumour clonal and phenotypic heterogeneity. However, the de novo identification of tumour subpopulations is so far both a challenging and an unresolved task. Here we present the first systematic approach for the de novo discovery of clinically detrimental molecular tumour subpopulations. In this proof-of-principle study, spatially resolved, tumour-specific mass spectra were acquired, using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry, from tissues of 63 gastric carcinoma and 32 breast carcinoma patients. The mass spectra, representing the proteomic heterogeneity within tumour areas, were grouped by a corroborated statistical clustering algorithm in order to obtain segmentation maps of molecularly distinct regions. These regions were presumed to represent different phenotypic tumour subpopulations. This was confirmed by linking the presence of these tumour subpopulations to the patients' clinical data. This revealed several of the detected tumour subpopulations to be associated with a different overall survival of the gastric cancer patients (p = 0.025) and the presence of locoregional metastases in patients with breast cancer (p = 0.036). The procedure presented is generic and opens novel options in cancer research, as it reveals microscopically indistinct tumour subpopulations that have an adverse impact on clinical outcome. This enables their further molecular characterization for deeper insights into the biological processes of cancer, which may finally lead to new targeted therapies. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.