Migration Networks

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”项目的研究旨在阐明肿瘤发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。本研究的重点是转移的四个方面：上皮细胞向间质转化（EMT）过程中获得运动表型，对生长因子刺激的运动反应，转移到中枢神经系统的传播以及对治疗的获得抗性。我们将使用数学模型来识别新的调控途径，当肿瘤细胞发展为侵袭性、转移性表型时，控制细胞行为。细胞在EMT中的行为和生长因子引起的运动将被定量测量。信号通路、基因表达和选择性剪接壁的状态将被询问，并用于采用综合系统方法来开发计算的、数据驱动的模型，将这些指标与细胞行为联系起来。这些模型将用于确定癌症从最初的侵袭到肿瘤细胞进入血液或淋巴管的转移过程中新的调控关系。转移通常导致对常规化疗和靶向治疗产生耐药性，可能是通过允许肿瘤细胞浸润受保护的微环境（如中枢神经系统）来逃避治疗。中枢神经的肿瘤细胞靶向

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.