Migration Networks

迁移网络

• 批准号: 8375826
• 负责人: FRANK B GERTLER
• 金额: $ 37.48万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-17 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8375826
• 关键词: Alternative Splicing; Behavior; Blood Vessels; Breast Cancer Cell; Carcinoma; Cause of Death; Cells; Data; Development; Disease; Distant; Gene Expression; Goals; Growth Factor; Lymphatic vessel; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Measures; Metric; Modeling; Neoplasm Metastasis; Neuraxis; Organ; Phenotype; Primary Neoplasm; RNA Interference; Regulation; Regulatory Pathway; Research; Resistance; Screening procedure; Signaling Pathway Gene; System; Therapeutic Intervention; Xenograft procedure; cell behavior; cell motility; chemotherapy; epithelial to mesenchymal transition; in vivo; mammary epithelium; mathematical model; migration; mortality; neoplastic cell; novel; programs; response; stem; therapy resistant; tumor; tumor progression

The central step in cancer progression that leads to mortality is metastasis, the dissemination of cells from the primary tumor mass to distant organs. Research in the "EMT, Migration and Metastasis Networks" program is aimed at elucidating the regulatory pathways governing tumor progression to full metastatic disease with the goal of identifying new targets for therapeutic intervention in the treatment of malignant cancers. The proposed research focuses on four general aspects of metastasis: acquisition of a motile phenotype during epithelial to mesenchymal transition (EMT), motility responses to growth factor stimulation, dissemination of metastasis to the CNS and acquisition of resistance to therapy. We will use mathematical modeling to indentify novel regulatory pathways that control cell behavior as tumor cells develop an invasive, metastatic phenotype. Cell behavior during EMT and growth factor elicited motility will be measured quantitatively. The status of signaling pathways, gene expression and alternative splicing wall be interrogated and used to take an integrative systems approach to develop computational, data-driven models that relate these metrics to cell behavior. The models will be used to identify novel regulatory relationships governing the steps in carcinoma metastasis from initial invasion to tumor cell entry into blood or lymphatic vessels. Metastasis often leads to the acquisition of resistance both to conventional chemotherapy and to target treatments, possibly by allowing tumor cells to evade treatment by infiltrating a protected microenvironment such as the central nervous system. Tumor cell targeting of the central nervous system and acquisition of therapy resistant phenotypes will be explored using high-throughput RNAi screening approaches in vivo in a lymphoma model. The research program will employ mammary epithelia cells, breast cancer cells, xenografts and syngeneic tumor models, and lymphoma.

导致死亡率的癌症进展的核心步骤是转移，这是细胞从原发性肿瘤质量到远处器官的传播。在“ EMT，迁移和转移网络”计划中进行的研究旨在阐明管理肿瘤发展为完全转移性疾病的调节途径，目的是确定用于治疗恶性癌症治疗治疗的新目标。拟议的研究集中于转移的四个一般方面：上皮过渡期间动向表型的获取（EMT），对生长因子刺激的运动响应，转移对CNS的传播以及对治疗耐药性的获取。我们将使用数学建模来辨认出新的调节途径，因为肿瘤细胞会发展出侵入性的转移性表型，从而控制细胞行为。 EMT期间的细胞行为和生长因子引发运动性将进行定量测量。询问信号通路，基因表达和替代剪接壁的状态，并用于采用集成系统方法来开发将这些指标与细胞行为相关联的计算，数据驱动的模型。这些模型将用于确定从初始侵袭到肿瘤细胞进入血液或淋巴管的癌转移癌转移步骤的新型调节关系。转移通常会导致对常规化疗和靶向治疗的抗性，这可能是通过允许肿瘤细胞通过渗透受保护的微环境（例如中枢神经系统）来逃避治疗的方法。中枢神经的肿瘤细胞靶向 在淋巴瘤模型中，将使用高通量RNAi筛选方法来探索系统和抗治疗表型的抗药性表型。该研究计划将采用乳腺上皮细胞，乳腺癌细胞，异种移植物和促肿瘤模型和淋巴瘤。