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的器官。“EMT、迁移和转移网络”计划的研究旨在阐明肿瘤向完全转移疾病发展的调控途径，目的是确定恶性肿瘤治疗干预的新靶点。目前的研究主要集中在转移的四个方面：上皮向间充质转化(EMT)过程中运动性表型的获得、对生长因子刺激的运动性反应、转移到中枢神经系统的转移和对治疗的抵抗。我们将使用数学模型来识别当肿瘤细胞发展为侵袭性、转移性表型时控制细胞行为的新的调控途径。在EMT过程中的细胞行为和生长因子诱导的运动将被定量测量。信号通路、基因表达和选择性剪接墙的状态被询问并用于采取综合系统的方法来开发将这些指标与细胞行为联系起来的计算的、数据驱动的模型。这些模型将被用来确定控制癌症转移过程中从最初侵袭到肿瘤细胞进入血管或淋巴管的步骤的新的调控关系。转移往往导致对常规化疗和靶向治疗产生抗药性，可能是通过允许肿瘤细胞通过渗透到受保护的微环境(如中枢神经系统)来逃避治疗。中枢神经肿瘤细胞靶向性研究 在淋巴瘤模型中，将使用高通量RNAi筛选方法来探索治疗耐药表型的系统和获得。该研究计划将使用乳腺上皮细胞、乳腺癌细胞、异种移植和同基因肿瘤模型以及淋巴瘤。

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.