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

• 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
• 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

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.

基质组织的癌细胞侵袭需要在主要组成部分之间进行复杂的相互作用 细胞骨架。该相互作用受细胞骨架调节剂的控制，该调节剂赋予了癌细胞的能力 动态改变其结构，以便在转移时通过基质组织入侵。确定 入侵的关键调节器，我是一支合作团队的一员，使用RNAi筛选来识别 癌细胞附着并侵袭内皮所需的途径。两个细胞骨架调节剂 从屏幕上出现时出现：角蛋白相关的蛋白5-5（KRTAP5-5）和MST3激酶。第一个 我的论文的一部分（AIM 1）涉及表征KRTAP5-5（角蛋白中间细丝的调节剂） 以前没有报道过癌症的作用，但我已经确定它是血管限制的 癌细胞的侵入性表型。我的剩余论文（AIM 2）现在专注于MST3 肌动蛋白细胞骨架调节剂是果蝇的五个已知哺乳动物MST同源物之一 河马激酶。该研究建议将首先探讨是否需要MST3激酶 三阴性乳腺癌细胞系的侵袭，MST3可能代表独特的假设 这种经常具有侵略性和治疗性抗性疾病的细胞骨架脆弱性。 MST3在基质中的作用 入侵将在经常用于预测转移性扩散的一系列模型中进行评估，其中之一是 尖端的微流体装置。 MST3和河马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淋巴结（即Rho and RAC）来研究。之上 完成，我的论文将对细胞骨架调节剂对癌症的影响产生不同的见解 基质的细胞入侵。毕业后，我寻求扩大我在肿瘤肿瘤方面的研究经验 串扰包括免疫系统的细胞（AIM 3），并计划继续我作为博士后的教育 研究员。