Full Project 1: Defining Mechanisms of MICAL-dependent Pancreatic Cancer Cell Migration

完整项目 1：MICAL 依赖性胰腺癌细胞迁移的定义机制

基本信息

批准号：
10762273
负责人：
ANDREW M LOWY
金额：
$ 18.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762273
关键词：
3-Dimensional Acetylation Actins Adherence Adhesions Adhesiveness Affect African American American Behavior Binding Biochemical Biology Biophysics Cause of Death Cell Adhesion Cell Cycle Progression Cell Nucleus Cell Proliferation Cell model Cells Chemotherapy-Oncologic Procedure Collaborations Cytoplasm Cytoskeleton Cytosol Data Development Disease Disease Progression Enhancers Environment Excision Extracellular Matrix F-Actin Flavins G Actin Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Goals Hispanic Hospitals Human Impairment Incidence Insurance Integrins Invaded Knowledge Laboratories Life Link Liver Lung Malignant Neoplasms Malignant neoplasm of pancreas Maps Mechanics Mixed Function Oxygenases Morbidity - disease rate Myosin ATPase Neoplasm Metastasis Not Hispanic or Latino Nuclear Nuclear Export Nucleic Acid Regulatory Sequences Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pattern Phenotype Play Pre-Clinical Model Primary Neoplasm Property Proteins Reporting Role Serum Response Factor Signal Induction Signal Transduction Socioeconomic Status Stromal Cells Structure Testing Transcription Coactivator Transcriptional Regulation alpha Actin anticancer research biophysical properties cancer cell cancer education cell motility depolymerization effective therapy experience extracellular health equity high risk population human disease improved improved outcome in vivo mechanical properties migration mortality myocardin new therapeutic target novel therapeutic intervention pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic stellate cell patient population screening therapeutic target therapeutically effective transcription factor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY/ ABSTRACT – PROJECT 1 Pancreatic duct adenocarcinoma (PDAC) takes the life of an American approximately every 12 minutes and disproportionately affects African American and Hispanic patients, who experience higher rates of morbidity and mortality compared to non-Hispanic white patients. Since the incidence of PDAC is relatively modest, even among higher risk groups, screening is not feasible. Thus, improvements in outcomes require an improved understanding of PDAC biology to guide development of effective therapies. Here, the partnering PI’s complementary expertise in PDAC biology and modeling cellular biophysical properties converge to investigate mechanisms of PDAC cell migration and metastasis, the primary cause of death in this patient population. The Lowy laboratory focused on identifying therapeutic targets by performing unbiased discovery in PDAC vs. normal pancreas. They hypothesized that super enhancer associated genes, which define cell identity, would be effective therapeutic targets for PDAC. One differentially acetylated enhancer region was mapped to the MICAL2 gene, that encodes a flavin monooxygenase. This protein drives F-actin depolymerization, that in the cytosol can restructure the actin myosin machinery used to migrate and respond to external mechanical and biochemical signals. MICAL2 also plays a role in linking nuclear actin dynamics to serum response factor (SRF) transcription. Myocardin-related transcription factors (MTRFs) are co-activators of SRF; when nuclear actin depolymerization is induced by MICAL2, globular actin is targeted for nuclear export, freeing MTRF to bind SRF and activate transcription of genes important for cell adhesion and migration. Studies in PDAC cells reveal that silencing MICAL2 expression impairs cell migration and metastasis. The Katira laboratory in collaboration with Dr. Engler’s group have reported that cell adhesiveness serves as a biophysical marker for metastatic potential, and both adhesiveness and contractility enable adurotaxis, the ability of cells to migrate regardless of a stiffness gradient. To goal of this project is to define how MICAL2 influences properties of adhesiveness and durotaxis, and how it may regulate properties, not only of the cancer cell, but of the tumor microenvironment through regulation of gene expression. We hypothesize that MICAL2 promotes PDAC cell invasion and metastasis by cell autonomous and non-cell autonomous mechanisms. We will test this hypothesis in three specific aims; 1) Determine how MICAL2 modulates adherence and durotaxis in pancreatic cancer cells, 2) Determine how MICAL2 promotes pancreatic cancer cell migration and metastasis, and 3) Determine how MICAL2 related signaling from cancer an stromal cells modulates the tumor microenvironment. As a putative therapeutic target, our goal is to determine how MICAL2 functionally regulates cell migration and metastatic capacity during PDAC progression. This knowledge will be key to understanding how and when MICAL2 activity can be targeted in PDAC.

项目摘要/摘要 – 项目 1 大约每 12 分钟就有一名美国人死于胰管腺癌 (PDAC) 对非裔美国人和西班牙裔患者的影响尤为严重，他们的发病率较高与非西班牙裔白人患者相比，PDAC 的发病率相对较低。在高风险人群中，筛查是不可行的，因此，要改善结果就需要改进。了解 PDAC 生物学，以指导有效疗法的开发。 PDAC 生物学和细胞生物物理特性建模方面的互补专业知识汇聚在一起进行研究 PDAC 细胞迁移和转移的机制，这是该患者群体死亡的主要原因。 Lowy 实验室专注于通过在 PDAC 与 PDAC 对比中进行公正的发现来确定治疗靶点。他们寻找定义细胞身份的超级增强子相关基因。一个差异乙酰化增强子区域被定位到 PDAC 的有效治疗靶点。 MICAL2 基因，编码黄素单加氧酶，该蛋白驱动 F-肌动蛋白解聚，即在胞质溶胶可以重组肌动蛋白肌球蛋白机制，用于迁移和响应外部机械和 MICAL2 还在将核肌动蛋白动力学与血清反应因子联系起来方面发挥着作用。 (SRF) 转录。心肌素相关转录因子 (MTRF) 是 SRF 的共激活因子； MICAL2 诱导肌动蛋白解聚，球状肌动蛋白靶向核输出，释放 MTRF 结合 SRF 并激活对 PDAC 细胞的细胞粘附和迁移研究重要的基因转录。揭示沉默 MICAL2 表达会损害细胞迁移和转移。 Katira 实验室与 Engler 博士的研究小组合作报告称，细胞粘附性是一种转移潜力的生物物理标记，粘附性和收缩性都使 adurotaxis 成为可能无论硬度梯度如何，细胞都能迁移的能力该项目的目标是定义 MICAL2 如何迁移。影响粘附性和硬度的特性，以及它如何调节特性，而不仅仅是癌症的特性细胞，而是通过基因表达的调节来影响肿瘤微环境。通过细胞自主和非细胞自主促进PDAC细胞侵袭和转移我们将通过三个具体目标来检验这一假设；1) 确定 MICAL2 如何调节。胰腺癌细胞的粘附和杜罗趋化，2) 确定 MICAL2 如何促进胰腺癌细胞迁移和转移，以及 3) 确定来自癌症和基质细胞的 MICAL2 相关信号传导如何作为假定的治疗靶点，我们的目标是确定 MICAL2 如何调节肿瘤微环境。这些知识将在 PDAC 进展过程中功能性地调节细胞迁移和转移能力。理解如何以及何时在 PDAC 中靶向 MICAL2 活性的关键。