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Reducing Metastatic Potential by Targeting Tumor Metabolism and Understanding the Free-floating Tumor Microenvironments of Metastasis.

机译：通过靶向肿瘤代谢并了解自由转移的肿瘤微环境转移来降低转移潜能。

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摘要

The dynamic balance between microtubule extension and actin contraction regulates mammalian cell shape, division and motility, which has made the cytoskeleton an attractive and very successful target for cancer drugs. Circulating breast tumor cells use tubulin-based structures known as microtentacles (McTNs) to re-attach to endothelial cells and arrest in distant organs. McTN formation is dependent on the opposing cytoskeletal forces of stable microtubules and the actin network. Numerous compounds in clinical use to reduce tumor growth indiscriminately alter the assembly and dynamics of all microtubules, which causes significant dose-limiting toxicities on normal tissues. Therefore, novel molecular targets on microtubules are necessary to better exploit the cytoskeleton of circulating tumor cells (CTCs). AMP- activated protein kinase (AMPK) is a cellular metabolic regulator that can alter actin and microtubule organization in epithelial cells. We used drugs targeting AMPK to better understand the role of this pathway on the cytoskeleton of breast tumor cells. AMPK inhibition increased both microtubule stability and cofilin activation, which also resulted in higher McTN formation and re-attachment. Conversely, AMPK activation decreased microtubule stability and coflin activation with concurrent decreases in McTN formation and cell re-attachment. We also investigated a downstream substrate of AMPK, clip-170, which is a microtubule end-binding protein. We found that constitutive phosphorylation of clip-170 also reduces McTN frequency. These results support a model where AMPK activators may be used therapeutically to reduce the metastatic efficiency of CTCs. However, effective strategies to study the free-floating behavior of freshly isolated CTCs from patients remains a major barrier limiting our understanding of CTC biology. Therefore, we engineered a strategy to spatially immobilize detached tumor cells while maintaining their free-floating character. The goal was achieved using a microfluidic cell tethering device that allows capture of high-resolution images of McTNs on viable free-floating cells. In addition, we showed that tethering allows for real-time analysis of McTN dynamics on individual tumor cells and in response to tubulin-targeting drugs. The ability to image detached tumor cells and test existing drugs can enhance our understanding of CTCs, improve the development of more precise cytoskeletal cancer therapies, and advance personalized cancer treatment for patients.
机译：微管延伸和肌动蛋白收缩之间的动态平衡调节哺乳动物细胞的形状，分裂和运动性，这使细胞骨架成为抗癌药物的诱人且非常成功的靶标。循环的乳腺肿瘤细胞使用基于微管蛋白的结构（称为微触角（McTNs））重新附着于内皮细胞并停滞在远处的器官中。 McTN的形成取决于稳定的微管和肌动蛋白网络的相反细胞骨架力。临床上用于减少肿瘤生长的多种化合物会不加选择地改变所有微管的组装和动力学，从而对正常组织产生明显的剂量限制性毒性。因此，微管上的新型分子靶标是更好地利用循环肿瘤细胞（CTC）的细胞骨架所必需的。 AMP激活蛋白激酶（AMPK）是一种细胞代谢调节剂，可以改变上皮细胞中的肌动蛋白和微管组织。我们使用了针对AMPK的药物，以更好地了解该途径在乳腺肿瘤细胞的细胞骨架中的作用。 AMPK抑制增加了微管的稳定性和cofilin激活，这还导致更高的McTN形成和重新连接。相反，AMPK激活降低了微管稳定性和coflin激活，同时减少了McTN的形成和细胞的重新附着。我们还研究了AMPK的下游底物clip-170，它是一种微管末端结合蛋白。我们发现clip-170的组成型磷酸化也降低了McTN频率。这些结果支持了一个模型，其中AMPK激活剂可用于治疗，以降低CTC的转移效率。但是，研究来自患者的新鲜分离的四氯化碳自由流动行为的有效策略仍然是限制我们对四氯化碳生物学认识的主要障碍。因此，我们设计了一种策略，可以在空间上固定分离的肿瘤细胞，同时保持其自由漂浮的特性。使用微流控细胞束缚设备可以实现该目标，该设备可以捕获活的自由漂浮细胞上的McTNs高分辨率图像。此外，我们证明了系留可以实时分析单个肿瘤细胞上的McTN动态以及对微管蛋白靶向药物的反应。对分离的肿瘤细胞成像并测试现有药物的能力可以增强我们对CTC的了解，改善更精确的细胞骨架癌治疗方法的开发，并推进针对患者的个性化癌症治疗。

著录项

  • 作者

    Chakrabarti, Kristi R.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Oncology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 194 p.
  • 总页数 194
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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