Impact of Cytoskeletal Regulators on Cancer Cell Stromal Invasion

癌细胞侵入间质组织需要癌细胞主要成分之间复杂的相互作用。 细胞骨架这种相互作用由细胞骨架调节剂控制，细胞骨架调节剂赋予癌细胞以下能力： 动态地改变它们的结构，以便在转移时通过基质组织侵入。以确定 作为入侵的关键调节剂，我是一个合作团队的一员，该团队采用RNAi筛选来识别 癌细胞附着和侵入内皮所需的途径。两种细胞骨架调节因子 出现在筛选的最高命中：角蛋白相关蛋白5-5（Krtap 5 -5）和MST 3激酶。第一 我的论文（目标1）中有一部分涉及到对Krtap 5 -5的特性分析，它是一种角蛋白中间丝的调节剂 以前没有报道过它在癌症中的作用，但我已经确定它是血管紧张素转换酶的限速酶。 癌细胞的侵袭表型。我论文的其余部分（目标2）现在重点关注MST 3，一个 肌动蛋白细胞骨架调节因子，是果蝇的五种已知哺乳动物MST同源物之一 河马激酶。这项研究计划将首先探讨MST 3激酶是否是基质细胞所必需的。 三阴性乳腺癌细胞系的侵袭，假设MST 3可能代表了一种独特的 细胞骨架的脆弱性，这种往往侵略性和治疗耐药的疾病。MST 3在基质中的作用 将在一系列常用于预测转移扩散的模型中评估侵袭，其中之一是 尖端的微流体装置MST 3和Hippo信号通路之间的潜在串扰也将 通过关注肌动蛋白细胞骨架的重要信号节点，即Rho和Rac来研究。后 完成后，我的论文将产生独特的见解，细胞骨架调节剂对癌症的影响 间质的细胞侵入。毕业后，我寻求扩大我的研究经验，在肿瘤间质 我的计划是将免疫系统的细胞包括在内（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.