Brain-Specific Metastasis Genes

四分之一的肺腺癌患者会发生脑转移。中枢神经 在靶向EGFR的药物取得初步成功后，该系统也正在成为首次复发的主要场所。 尽管接受了治疗，但三分之二的脑转移瘤患者出现了神经症状和 许多人死于肺癌的这种表现。脑转移的动物模型系统很少。作为一名 结果，人们对使肺腺癌细胞在体内定植的基因和功能知之甚少 大脑。我们已经将基于无偏DNA阵列的基因表达谱与体内表达的能力结合在一起 器官特异性转移细胞的功能选择以确定调节器官特异性的基因 转移。我们之前在乳腺癌转移的研究中验证了这一实验策略 骨头和肺。到目前为止，我们的结果表明，肿瘤细胞利用不同的基因集来定植不同的 器官。我们正在将这种方法应用于肺腺癌细胞的脑转移问题。通过 从H2030肺腺癌细胞中体内选择脑转移亚群的方法，以及 对比转录分析，我们已经确定了一个肺到脑转移的特征，包括 其表达与脑转移行为有关的基因。在这项前期工作的基础上，我们将 将肺癌脑特异性转移基因的鉴定扩展到其他KRAS突变和EGFR 突变细胞系，以及MSKCC胸腔积液和纵隔淋巴结中的恶性细胞 病人。我们将在小鼠的脑转移实验中从功能上验证脑特异性转移基因。在……里面 与Marc Ladanyi(核心A)合作，我们将确定实验性肺对脑的关联 肿瘤转移标志与脑转移的临床转归。我们将确定哪个肺-对- 脑转移标志基因介导血脑屏障的破坏和脑的侵袭 薄壁组织。基于这些细胞系和基因，我们将开发临床前模型来测试 Harold Varmus(Rp4)研究的治疗药物的有效性和耐药性，William Pao (RP3)和尼尔·罗森(RP2)。因此，我们将结合独特的实验方法、新技术 并在该计划项目中进行补充合作，以确定肺的决定因素 腺癌脑转移及其对治疗干预的易感性。

One quarter of persons with adenocarcinoma of the lung develop brain metastases. The central nervous system is also emerging as a major site of first relapse after initial success with drugs targeting EGFR. Despite treatment, two thirds of patients with cerebral metastases experience neurological symptoms and many succumb to this manifestation of lung cancer. Animal model systems of brain metastasis are few. As a result, little is known about the genes and functions that enable lung adenocarcinomacells to colonize the brain. We have combined the power of unbiased DNA array-based profiling of gene expression with in vivo functional selection of organ-specific metastatic cells to identify genes that mediate organ-specific metastasis. We previously validated this experimental strategy in studies on breast cancer metastasis to bone and lung. Our results to date show that tumor cells utilize different sets of genes to colonize different organs. We are applying this approach to the problem of brain metastasis by lung adenocarcinoma cells. By means of in vivo selection of brain metastatic subpopulations from H2030 lung adenocarcinoma cells, and comparative transcriptomic analysis, we have identified a lung-to-brain metastasis signature consisting of genes whose expression is linked to brain metastatic behavior. Building on this preliminary work, we will expand the identification of brain-specific lung cancer metastasis genes to other KRAS mutant and EGFR mutant cell lines, and to malignant cells from pleural effusions and mediastinal lymph nodes from MSKCC patients. We will functionally validate brain-specific metastasis genes in brain metastasis assays in mice. In collaboration with Marc Ladanyi (Core A), we will determine the association of the experimental lung-to-brain metastasis signature with the clinical outcome of brain metastasis. We will determine which of the lung-to- brain metastasis signature genes mediate disruption of the blood brain barrier and invasion of the brain parenchyma. Based on these cell lines and genes we will develop preclinical models for testing the effectiveness of, and resistance to, the therapeutic agents studied by Harold Varmus (RP4), William Pao (RP3), and Neal Rosen (RP2). Thus, we will combine unique experimental approaches, novel technologies and complementary collaborations within this Program Project to identify the determinants of lung adenocarcinoma brain metastasis and its susceptibility to therapeutic intervention.