Heterogeneity of Pancreatic Cancer Metastases in a Single Patient Revealed by Quantitative Proteomics
Heterogeneity of Pancreatic Cancer Metastases in a Single Patient Revealed by Quantitative Proteomics
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DOI：
10.1074/mcp.m114.038547
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发表时间：
2014-11-01
影响因子：
7
通讯作者：
Pandey, Akhilesh
中科院分区：
文献类型：
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作者：
Kim, Min-Sik;Zhong, Yi;Pandey, Akhilesh
许多胰腺癌患者在初次就诊时已转移到远处器官。最近的研究在基因水平上检查胰腺癌的演变已经表明，转移性胰腺癌的克隆复杂性已经在原发性肿瘤内开始，并且器官特异性转移来源于不同的亚克隆。然而，我们还不知道胰腺癌的演变在多大程度上有助于蛋白质组和信号改变。我们假设转移性胰腺癌的遗传异质性导致蛋白质组水平的异质性。为了解决这个问题，我们采用了一个模型系统，其中比较了从单个患者的三个转移部位（肝、肺和腹膜）分离的细胞。我们使用基于SILAC的精确定量蛋白质组学策略结合高分辨率质谱分析每个远端转移瘤的总蛋白质组和酪氨酸磷酸化蛋白质组。我们的数据揭示了在三种不同的转移性病变中，整体蛋白质组表达和酪氨酸激酶活性的不同模式。这种异质性是显著的，因为它导致肿瘤细胞对靶向各种激酶和其他途径的小分子抑制剂的不同敏感性。例如，靶向Axl受体酪氨酸激酶的酪氨酸激酶抑制剂R428能够比来自腹膜转移的细胞更有效地抑制来自肺和肝转移的细胞。最后，我们证实，与源自腹膜转移细胞系的肿瘤相比，在携带源自三个不同转移部位的细胞的异种移植物的小鼠中施用R428显著减少了源自肝和肺转移细胞系的肿瘤。总的来说，我们的数据提供了原理证明支持，即单个患者多器官转移的个性化治疗应涉及药物组合的给药，每种药物针对不同亚克隆的特征。
Many patients with pancreatic cancer have metastases to distant organs at the time of initial presentation. Recent studies examining the evolution of pancreatic cancer at the genetic level have shown that clonal complexity of metastatic pancreatic cancer is already initiated within primary tumors, and organ-specific metastases are derived from different subclones. However, we do not yet understand to what extent the evolution of pancreatic cancer contributes to proteomic and signaling alterations. We hypothesized that genetic heterogeneity of metastatic pancreatic cancer results in heterogeneity at the proteome level. To address this, we employed a model system in which cells isolated from three sites of metastasis (liver, lung, and peritoneum) from a single patient were compared. We used a SILAC-based accurate quantitative proteomic strategy combined with high-resolution mass spectrometry to analyze the total proteome and tyrosine phosphoproteome of each of the distal metastases. Our data revealed distinct patterns of both overall proteome expression and tyrosine kinase activities across the three different metastatic lesions. This heterogeneity was significant because it led to differential sensitivity of the neoplastic cells to small molecule inhibitors targeting various kinases and other pathways. For example, R428, a tyrosine kinase inhibitor that targets Axl receptor tyrosine kinase, was able to inhibit cells derived from lung and liver metastases much more effectively than cells from the peritoneal metastasis. Finally, we confirmed that administration of R428 in mice bearing xenografts of cells derived from the three different metastatic sites significantly diminished tumors formed from liver- and lung-metastasis-derived cell lines as compared with tumors derived from the peritoneal metastasis cell line. Overall, our data provide proof-of-principle support that personalized therapy of multiple organ metastases in a single patient should involve the administration of a combination of agents, with each agent targeted to the features of different subclones.