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中心步骤是转移，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。拟议的研究集中在四个一般方面的转移：收购的上皮间质转化（EMT）期间的能动性表型，运动反应生长因子刺激，转移到中枢神经系统的传播和收购的耐药性治疗。我们将使用数学建模来确定新的调控途径，控制细胞行为的肿瘤细胞发展的侵袭性，转移性表型。将定量测量EMT期间的细胞行为和生长因子引起的运动。信号通路、基因表达和可变剪接的状态可以被询问并用于采取综合系统方法来开发将这些度量与细胞行为相关联的计算的、数据驱动的模型。该模型将用于确定新的调节关系，从最初的入侵到肿瘤细胞进入血液或淋巴管的癌转移的步骤。转移通常导致获得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浸润受保护的微环境（如中枢神经系统）来逃避治疗。中枢神经系统肿瘤细胞靶向 将在淋巴瘤模型中使用体内高通量RNAi筛选方法来探索系统和治疗抗性表型的获得。该研究计划将采用乳腺上皮细胞，乳腺癌细胞，异种移植和同源肿瘤模型，淋巴瘤。