Brain-Specific Metastasis Genes

脑特异性转移基因

• 批准号: 7315927
• 负责人: JOAN MASSAGUE
• 金额: $ 28.48万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315927
• 关键词: Adenocarcinoma Cell; Aftercare; Animal Model; Behavior; Biological; Biological Assay; Biological Models; Blood - brain barrier anatomy; Brain; Cell Communication; Cell Line; Cells; Cerebrum; Clinical; Collaborations; DNA; Data Set; Disease; Disruption; Drug Delivery Systems; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; Equipment; Event; Extravasation; Gene Expression; Gene Targeting; Gene Transfer; Genes; Human Resources; Image; Immunodeficient Mouse; KRAS2 gene; Laboratory Procedures; Link; Lung; Lung Adenocarcinoma; Malignant neoplasm of lung; Mediastinal lymph node group; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Metastatic Lesion; Metastatic Neoplasm to the Bone; Metastatic malignant neoplasm to brain; Modeling; Mus; Neoplasm Metastasis; Neuraxis; Neurologic; Non-Small-Cell Lung Carcinoma; Organ; Outcome; Patients; Persons; Pharmaceutical Preparations; Pleural effusion disorder; Pre-Clinical Model; Preclinical Testing; Predisposition; Primary Neoplasm; Proteins; Protocols documentation; Relapse; Research Ethics Committees; Resistance; Sampling; Site; Staging; Symptoms; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissue Procurements; Tissue Sample; Work; base; cancer cell; clinically relevant; comparative; experience; gene function; gene interaction; in vivo; inhibitor/antagonist; lymph nodes; malignant breast neoplasm; metastatic process; mutant; neoplastic cell; new technology; novel; prognostic; programs; response; scientific organization; success; transcriptomics; tumor

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.

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部位。 尽管接受治疗，三分之二的脑转移患者仍会出现神经系统症状 许多人死于肺癌的这种表现。脑转移的动物模型系统很少。作为一个 结果，人们对肺腺癌细胞能够定植于肺腺癌细胞的基因和功能知之甚少。 脑。我们将基于 DNA 阵列的基因表达分析与体内分析相结合 器官特异性转移细胞的功能选择，以确定介导器官特异性的基因 转移。我们之前在乳腺癌转移研究中验证了这一实验策略 骨和肺。迄今为止我们的结果表明肿瘤细胞利用不同的基因组来定植不同的 器官。我们正在将这种方法应用于解决肺腺癌细胞脑转移的问题。经过 从H2030肺腺癌细胞体内选择脑转移亚群的方法，以及 通过比较转录组分析，我们发现了肺到脑的转移特征，其中包括 其表达与脑转移行为相关的基因。在这项前期工作的基础上，我们将 将脑特异性肺癌转移基因的鉴定范围扩大到其他KRAS突变体和EGFR 突变细胞系，以及来自 MSKCC 胸腔积液和纵隔淋巴结的恶性细胞 患者。我们将在小鼠脑转移试验中对脑特异性转移基因进行功能验证。在 与 Marc Ladanyi（核心 A）合作，我们将确定实验肺与脑的关联 转移特征与脑转移的临床结果。我们将确定哪个肺到 脑转移特征基因介导血脑屏障破坏和大脑侵袭 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), William Pao 研究的治疗药物的有效性和耐药性 （RP3）和尼尔·罗森（RP2）。因此，我们将结合独特的实验方法、新技术 以及本计划项目内的互补合作，以确定肺的决定因素 腺癌脑转移及其对治疗干预的敏感性。