Impact of Cytoskeletal Regulators on Cancer Cell Stromal Invasion

细胞骨架调节剂对癌细胞基质侵袭的影响

基本信息

批准号：
10303071
负责人：
Eric Berens
金额：
$ 9.61万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-16 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303071
关键词：
3-Dimensional Actins Affect American Association of Cancer Research Behavior Blood Circulation Blood Vessels Breast Cancer Cell Breast Cancer cell line Cancer Model Cell Line Cell membrane Cell-Matrix Junction Cells Cellular Structures Collagen Complex Cytoskeleton Disease Resistance Distant Drops Drosophila genus Education Extracellular Matrix Extravasation Genes Goals Hair Homologous Gene Human Immune system Immunologist Immunology Immunotherapy Institutes Integrin beta4 Intermediate Filaments Invaded Keratin Knowledge LATS1 gene Laboratories Learning Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Manuscripts Methods Microfluidic Microchips Microfluidics Microtubules Modeling Monitor Neoplasm Metastasis Oncogenes Organ Pathway interactions Phenotype Phosphotransferases Physiological Positioning Attribute Proteins Publishing RNA interference screen Regulation Reporting Research Research Personnel Research Proposals Role Scientist Series Shapes Signal Pathway Signal Transduction Stromal Invasion Stromal Neoplasm Structure Therapeutic Tissues Training Transcription Coactivator Tumor Suppressor Proteins Up-Regulation Vimentin Work Zebrafish aggressive breast cancer cancer cell cancer invasiveness cell motility crosslink experience in vitro Model innovation insight interest matrigel meetings novel recruit rho triple-negative invasive breast carcinoma tumor tumor immunology

项目摘要

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.

癌细胞侵入基质组织需要基质组织的主要成分之间复杂的相互作用细胞骨架。这种相互作用受到细胞骨架调节因子的控制，细胞骨架调节因子赋予癌细胞以下能力：动态改变其结构，以便在转移时侵入基质组织。确定入侵的关键调节剂，我是一个协作团队的成员，该团队采用 RNAi 筛选来识别癌细胞附着并侵入内皮细胞所需的途径。两个细胞骨架调节因子屏幕上最热门的两个蛋白是：角蛋白相关蛋白 5-5 (Krtap5-5) 和 MST3 激酶。第一个我论文的一部分（目标 1）涉及表征 Krtap5-5，一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的速率限制癌细胞的侵袭表型。我论文的其余部分（目标 2）现在重点关注 MST3，一个肌动蛋白细胞骨架调节剂，是果蝇五种已知的哺乳动物 MST 同源物之一河马激酶。该研究计划将首先探讨基质细胞是否需要 MST3 激酶。三阴性乳腺癌细胞系的侵袭，假设 MST3 可能代表一种独特的这种通常具有侵袭性和治疗耐药性的疾病的细胞骨架脆弱性。 MST3 在基质中的作用侵袭将在一系列通常用于预测转移扩散的模型中进行评估，其中一个是最先进的微流体装置。 MST3 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 进行研究。之上完成后，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细胞侵入间质。毕业后，我寻求扩大我在肿瘤间质方面的研究经验串扰包括免疫系统细胞（目标 3）并计划继续我的博士后教育研究员。