Systems Bioengineering of Cancer Cell Migration

 描述（由申请人提供）：恶性细胞向一种或多种信号分子梯度的定向迁移是转移的基本步骤的基础，包括癌细胞的局部侵袭、血管内渗和癌细胞外渗 在第二个站点。理解在具有多个细胞和细胞外基质分子的复杂环境中梯度的形成仍然是细胞迁移的中心挑战，不仅在癌症中，而且在正常生理学和其他疾病中。在肿瘤的无序细胞和细胞外基质结构中，理解梯度形成和细胞迁移的挑战变得更加困难。我们将通过综合系统生物工程方法来应对这一挑战，该方法将细胞迁移的微尺度技术，体外和体内细胞和分子成像以及复杂的多尺度计算模型相结合。这种方法将使我们能够在越来越复杂的环境中研究梯度形成和细胞迁移，从具有三种不同细胞类型的定义位置的2D系统到肿瘤的无序结构。使用计算建模来确定控制梯度形成和细胞迁移的关键参数，我们还将通过实验测试和验证阻断细胞迁移的干预措施，这将为抗转移治疗提供新的靶点。我们的研究将集中在趋化因子CXCL 12控制的梯度形成和细胞迁移，CXCL 12是一种驱动20多种人类癌症转移的信号分子。CXCL 12以六种选择性剪接亚型存在，其中四种在人类乳腺癌中表达。我们最近已经显示了CXCL 12亚型在细胞迁移、靶向抑制剂耐药性以及与乳腺癌复发和生存的相关性方面的特异性差异。我们建议，CXCL 12分子结合到细胞外环境驱动细胞迁移，一个过程称为haptotaxis，和差异结合到细胞外基质的基础异构体特异性差异梯度形成和细胞迁移。为了研究细胞迁移中的CXCL 12亚型，我们将完成以下具体目标：1）在简单的、定义的梯度下导出基本细胞迁移响应参数; 2）使用组织样几何形状，测试细胞外基质组成对CXCL 12亚型迁移效力的影响;和3）用不同的CXCL 12亚型定量肿瘤环境中的体内迁移。总的来说，这项研究将推进细胞迁移中梯度形成的知识，并指出针对癌症中CXCL 12的新治疗策略。

 DESCRIPTION (provided by applicant): Directional migration of malignant cells toward a gradient of one or more signaling molecules underlies fundamental steps in metastasis, including local invasion of cancer cells, vascular intravasation, and extravasation of cancer cells at secondary sites. Understanding formation of gradients in complex environments with multiple cells and extracellular matrix molecules remains a central challenge in cell migration not only in cancer but also in normal physiology and other diseases. The challenge of understanding gradient formation and cell migration becomes even more difficult in the disordered cellular and extracellular matrix architecture of a tumor. We will meet this challenge through an integrated systems bioengineering approach combining microscale technologies for cell migration, in vitro and in vivo cellular and molecular imaging, and sophisticated multi-scale computational models. This approach will enable us to investigate gradient formation and cell migration in increasingly complex environments, ranging from a 2D system with defined positions of three different cell types to the disorganized structure of a tumor. Using computational modeling to identify key parameters controlling gradient formation and cell migration, we also will experimentally test and validate interventions to block cell migration, which will provide new targets for anti-metastatic therapies. Our research will focus on gradient formation and cell migration controlled by chemokine CXCL12, a signaling molecule that drives metastasis in more than 20 human cancers. CXCL12 exists as six alternatively-spliced isoforms, four of which are expressed in human breast cancers. We recently have shown CXCL12-isoform specific differences in cell migration, resistance to targeted inhibitors, and correlations with disease recurrence and survival in breast cancer. We propose that CXCL12 molecules bound to the extracellular environment drive cell migration, a process referred to as haptotaxis, and differences in binding to the extracellular matrix underlie isoform-specific differences in gradient formation and cell migration. To investigate CXCL12 isoforms in cell migration, we will complete the following specific aims: 1) derive basic cell migration response parameters under simple, defined gradients; 2) using tissue-like geometries, test effects of extracellular matrix composition on migration potency of CXCL12 isoforms; and 3) Quantify in vivo migration in tumor environments with different CXCL12 isoforms. Collectively, this research will advance knowledge of gradient formation in cell migration and point to new treatment strategies for targeting CXCL12 in cancer.