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.

导致死亡的癌症进展的核心步骤是转移，即细胞从原发肿瘤块扩散到远处器官。 “EMT、迁移和转移网络”计划的研究旨在阐明控制肿瘤进展为完全转移性疾病的调控途径，目的是确定恶性癌症治疗干预的新靶点。拟议的研究重点关注转移的四个一般方面：上皮间质转化（EMT）过程中运动表型的获得、对生长因子刺激的运动反应、转移瘤向中枢神经系统的扩散以及对治疗的耐药性的获得。我们将使用数学模型来确定当肿瘤细胞发展出侵袭性、转移性表型时控制细胞行为的新调控途径。将定量测量 EMT 期间的细胞行为和生长因子引发的运动。信号通路、基因表达和选择性剪接壁的状态被询问并用于采用综合系统方法来开发将这些指标与细胞行为联系起来的计算、数据驱动模型。该模型将用于确定控制癌症转移从最初侵袭到肿瘤细胞进入血管或淋巴管的步骤的新调控关系。转移通常会导致对常规化疗和靶向治疗产生耐药性，这可能是因为肿瘤细胞通过渗透受保护的微环境（如中枢神经系统）来逃避治疗。肿瘤细胞靶向中枢神经 将在淋巴瘤模型中使用体内高通量 RNAi 筛选方法来探索治疗耐药表型的系统和获得。该研究计划将采用乳腺上皮细胞、乳腺癌细胞、异种移植物和同基因肿瘤模型以及淋巴瘤。