Molecular mechanisms initiating cell migrations in Caonorhabditis elegans

秀丽隐杆线虫细胞迁移的分子机制

基本信息

批准号：
9305063
负责人：
Martha C Soto
金额：
$ 33.39万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305063
关键词：
ANGPTL2 gene Actins Address Adhesions Animal Model Apical Basement membrane Basic Science Biochemistry Biological Markers Biological Models Caenorhabditis elegans Cell Adhesion Cell Polarity Cell Surface Receptors Cell membrane Cell physiology Cells Cellular Structures Colon Carcinoma Colorectal Cancer Communication Complex Cytoskeleton Defect Dependence Development Disease Disseminated Malignant Neoplasm ECM receptor Embryo Embryonic Development Ephrins Epidermis Epithelial Epithelial Cells Extracellular Matrix F-Actin Failure Funding GTPase-Activating Proteins Genes Genetic Genetic Screening Goals Growth Guanosine Triphosphate Phosphohydrolases Hand Heart Diseases Homologous Gene Human Human Development Knock-out Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Metastatic breast cancer Metastatic to Modeling Molecular Monomeric GTP-Binding Proteins Morphogenesis Muscle Muscle Cells Mutation Neoplasm Metastasis Phenotype Play Process Proteins Recruitment Activity Regulation Research Design Role Signal Pathway Signal Transduction Structure Supporting Cell System Testing Tissues Transgenes Vesicle Work anticancer research axonal guidance blastomere structure cell growth regulation cell motility clinically relevant extracellular human disease in vivo in vivo Model lung metastatic migration mutant null mutation polarized cell prevent public health relevance receptor trafficking triple-negative invasive breast carcinoma tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cancer progression and metastasis require changes in cell polarity that drives changes in cellular adhesion and motility. Adhesion and motility are regulated by the polarized actin cytoskeleton. Our long-term goal is to identify the mechanisms that polarize actin during healthy growth and during disease. We have used the model organism C. elegans to study cell movements during embryonic development. Using knockout mutants we have shown that loss of regulators of actin nucleation including the GTPase CED-10/Rac1, any component of the actin nucleating Arp2/3 complex, or of its activator, the WAVE/SCAR complex, results in the same phenotype: failure in embryonic cell migrations, morphogenesis and altered epithelial polarity. Mutations in the conserved WAVE/SCAR complex are associated with cancers including aggressive metastatic cancers. For example, WAVE2 is misexpressed in malignant lung cancers and metastatic colorectal cancers (Semba et al. 2006; Iwaya et al. 2007). However, how the actin cytoskeleton is regulated during normal growth or misregulated during metastasis is not well understood. We have recently identified extracellular signals that regulate Rac1/CED-10 and WAVE/SCAR during embryonic cell migrations. With these upstream signals in hand we want to address the following hypothesis for how outside signals polarize F-actin: Objective/Hypothesis: We hypothesize that distinct signals at the plasma membrane activate the WAVE/SCAR complex to promote cell polarization, and that the extracellular receptors we have identified play an important role in both signaling between cells, and in transmitting signals intracellularly to polarize cellular F-actin. Specific Aims: (1) To tes the model that ECM (extra cellular matrix) receptors support epithelial cell migrations by regulating WAVE at the apical junction. (2) To determine if signaling between tissues organizes F-actin in epidermal cells. (3) To test the model that ECM receptors act through the regulation of specific Rac GAPs. Study Design: In Aim 1 we use our in vivo system to determine both how WAVE is recruited to apical junction and what role it plays there to better understand how WAVE/SCAR promotes cell polarity. In Aim 2 we create an in vivo model for testing how tissues detect the polarized state of F-actin in neighboring tissues. In Aim 3 we use genetics and biochemistry to identify the GAP proteins that regulate Rac/CED-10 during embryonic morphogenesis. Clinical relevance: The human homolog of one of the genes we study in C. elegans, WAVE3, is considered a biomarker for high grade, triple negative breast cancer (Kulkarni et al., 2012) and is associated with invasive prostate and colon cancers (Fernando et al., 2010; Zhang et al., 2012). Understanding the molecules that regulate actin dynamics through the WAVE/SCAR complex during cell migrations will not only enlighten our understanding of normal development but could suggest new biomarkers for altered actin regulation in human disease.

描述（由申请人提供）：癌症进展和转移需要细胞极性的变化，从而驱动细胞粘附和运动的变化。粘附和运动受极化肌动蛋白细胞骨架的调节。我们的长期目标是确定健康生长和疾病期间肌动蛋白极化的机制。我们使用模型生物秀丽隐杆线虫来研究胚胎发育过程中的细胞运动。使用敲除突变体，我们发现肌动蛋白成核调节因子（包括 GTPase CED-10/Rac1）、肌动蛋白成核 Arp2/3 复合体的任何成分或其激活剂 WAVE/SCAR 复合体的丢失，会导致相同的表型：胚胎细胞迁移、形态发生和上皮极性改变的失败。保守的 WAVE/SCAR 复合体中的突变与癌症（包括侵袭性转移性癌症）相关。例如，WAVE2 在恶性肺癌和转移性结直肠癌中错误表达（Semba 等人，2006 年；Iwaya 等人，2007 年）。然而，肌动蛋白细胞骨架在正常生长过程中如何受到调节或在转移过程中如何被错误调节尚不清楚。我们最近发现了在胚胎细胞迁移过程中调节 Rac1/CED-10 和 WAVE/SCAR 的细胞外信号。有了这些上游信号，我们想要解决以下关于外部信号如何极化 F-肌动蛋白的假设：目的/假设：我们假设质膜上的不同信号激活 WAVE/SCAR 复合物以促进细胞极化，并且细胞外信号我们已经确定的受体在细胞间信号传导以及细胞内信号传递以极化细胞 F-肌动蛋白方面发挥着重要作用。具体目的：（1）测试ECM（细胞外基质）受体通过调节顶端连接处的WAVE来支持上皮细胞迁移的模型。 (2) 确定组织之间的信号传导是否组织表皮细胞中的 F-肌动蛋白。 (3)测试ECM受体通过调节特定Rac GAPs发挥作用的模型。研究设计：在目标 1 中，我们使用我们的体内系统来确定 WAVE 如何被招募到顶端连接以及它在那里发挥什么作用，以更好地了解 WAVE/SCAR 如何促进细胞极性。在目标 2 中，我们创建了一个体内模型，用于测试组织如何检测邻近组织中 F-肌动蛋白的极化状态。在目标 3 中，我们利用遗传学和生物化学来鉴定在胚胎形态发生过程中调节 Rac/CED-10 的 GAP 蛋白。临床相关性：我们在秀丽隐杆线虫中研究的基因之一的人类同源物 WAVE3 被认为是高级别三阴性乳腺癌的生物标志物（Kulkarni 等，2012），并且与侵袭性前列腺癌和结肠癌相关（费尔南多等人，2010；张等人，2012）。了解细胞迁移过程中通过 WAVE/SCAR 复合物调节肌动蛋白动力学的分子不仅可以启发我们对正常发育的理解，还可以为人类疾病中改变的肌动蛋白调节提出新的生物标志物。