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 胰管导管腺癌（PDAC）大约每12分钟占用美国人的生命不成比例地影响非裔美国人和西班牙裔患者，他们的发病率更高与非西班牙裔白人患者相比，死亡率和死亡率。由于PDAC的事件相对谦虚，甚至在较高的风险组中，筛查是不可行的。这是结果的改善需要改进了解PDAC生物学以指导有效疗法的开发。在这里，伙伴PI的 PDAC生物学和模拟细胞生物物理特性的互补专业知识融合了研究 PDAC细胞迁移和转移的机制，这是该患者人群死亡的主要原因。 Lowy实验室的重点是通过在PDAC VS中进行无偏见的发现来识别治疗靶标。正常胰腺。他们假设定义细胞身份的超级增强剂相关基因将是PDAC的有效治疗靶标。将一个不同的乙酰化增强子区域映射到 mical2基因，该基因编码黄素单加氧酶。该蛋白驱动F-肌动蛋白沉积，在细胞质可以限制用于迁移和响应外部机械和响应的肌动蛋白肌球蛋白机械和生化信号。 mical2还在将核肌动蛋白动力学与血清反应因子联系起来中起作用（SRF）转录。与心肌相关的转录因子（MTRF）是SRF的共激活因子；当核时肌动蛋白的沉积是由Mical2诱导的，全球肌动蛋白针对核出口，将MTRF释放到结合SRF并激活对细胞粘附和迁移重要的基因转录。 PDAC细胞的研究揭示沉默的mical2表达会损害细胞迁移和转移。 Katira实验室与Engler博士的小组合作报道说，细胞粘合剂可作为生物物理标志物的转移潜力，并且粘附性和收缩力使adurotaxis，细胞迁移的能力无论刚度梯度如何。该项目的目标是定义如何mical2 影响粘附性和杜罗可去的特性，以及它如何调节特性，不仅是癌症的特性细胞，但通过调节基因表达的肿瘤微环境。我们假设Mical2 促进细胞自主和非细胞自主的PDAC细胞侵袭和转移机制。我们将以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中的依从性和杜罗可去，2）确定mical2如何促进胰腺癌细胞迁移和转移，以及3）确定癌症中基质细胞的Mical2相关信号如何调节肿瘤微环境。作为推定的治疗靶标，我们的目标是确定Mical2如何在PDAC进展过程中，功能上调节细胞迁移和转移能力。这些知识将是了解如何以及何时可以在PDAC中靶向mical2活性的关键。