Impact of Cytoskeletal Regulators on Cancer Cell Stromal Invasion

癌细胞侵袭间质组织需要在主要成分之间复杂的相互作用 细胞骨架。这种相互作用是由细胞骨架调节器控制的，它赋予癌细胞 动态改变其结构，以便在转移时通过间质组织侵袭。要确定 作为入侵的关键调节因子，我是一个合作团队的成员，该团队利用RNAi筛选来识别 癌细胞附着和侵袭内皮细胞所需的途径。两种细胞骨架调节剂 屏幕上最热门的是：角蛋白相关蛋白5-5(Krap5-5)和MST3激酶。第一 我的论文的一部分(目标1)涉及角蛋白中间丝的调节剂Krtab5-5的特征 以前没有报道过它在癌症中的作用，但我已经确定它对血管是限速的 癌细胞的侵袭性表型。我论文的其余部分(目标2)现在集中在MST3，一个 肌动蛋白细胞骨架调节因子是已知的五种哺乳动物果蝇MST同源物之一 河马激活剂。这项研究计划将首先探讨MST3激酶是否是基质所必需的 三阴性乳腺癌细胞株的侵袭性，假设MST3可能代表一种独特的 对于这种通常具有侵袭性和治疗抗药性的疾病，细胞骨架的脆弱性。MST3中的S在基质中的作用 侵袭性将通过一系列通常用于预测转移扩散的模型进行评估，其中之一是 尖端微流控设备。MST3和河马信号通路之间的潜在串扰也将 通过重点研究肌动蛋白细胞骨架的重要信号节点，即Rho和Rac。vt.在.的基础上 完成后，我的论文将对细胞骨架调节剂对癌症的影响产生独特的见解 间质的细胞侵袭。毕业后，我寻求扩大我在肿瘤间质方面的研究经验 相声，包括免疫系统细胞(目标3)，并计划继续我的博士后教育 研究员。

Cancer cell invasion of stromal tissues requires a complex interplay between major components of the cytoskeleton. This interplay is governed by cytoskeletal regulators, which endow cancer cells with the ability to dynamically alter their structure in order to invade through stromal tissue when metastasizing. To determine critical modulators of invasion, I was part of a collaborative team that employed RNAi screening to identify pathways required for cancer cell attachment to, and invasion though, endothelia. Two cytoskeletal regulators emerged as top hits from the screen: keratin-associated protein 5-5 (Krtap5-5) and the MST3 kinase. The first part of my dissertation (Aim 1) involved characterizing Krtap5-5, a regulator of keratin intermediate filaments that had no previous reported role in cancer, yet I have determined that it is rate-limiting for the vascular invasive phenotype of cancer cells. The remainder of my dissertation (Aim 2) is now focused on MST3, an actin cytoskeleton regulator that is one of the five known mammalian MST homologues of the Drosophila Hippo kinase. This research proposal will first explore whether the MST3 kinase is required for stromal invasion by triple-negative breast cancer cell lines, with the hypothesis that MST3 may represent a unique cytoskeletal vulnerability for this often aggressive and therapeutically resistant disease. MST3's role in stromal invasion will be assessed in a series of models often used to predict metastatic spread, one of which is a cutting-edge microfluidic device. Potential crosstalk between MST3 and the Hippo signaling pathway will also be studied by focusing on important signaling nodes of the actin cytoskeleton, namely Rho and Rac. Upon completion, my dissertation will produce distinct insights into the impact of cytoskeletal regulators on cancer cell invasion of the stroma. After graduating, I seek to expand my research experience in tumor-stromal crosstalk to include cells of the immune system (Aim 3) and plan to continue my education as a postdoctoral researcher.