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

项目 1：定义 MICAL 依赖性胰腺癌细胞迁移机制

• 批准号: 10762144
• 负责人: Parag Katira
• 金额: $ 16.96万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762144
• 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

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.

项目总结/摘要-项目1 胰管腺癌（PDAC）大约每12分钟就夺走一个美国人的生命， 不成比例地影响非洲裔美国人和西班牙裔患者，他们的发病率更高 与非西班牙裔白色患者相比，由于PDAC的发病率相对较低，即使 至于高危组别，则不适宜接受检查。因此，成果的改善需要改进 了解PDAC生物学，以指导有效疗法的开发。在这里，合作PI的 PDAC生物学和建模细胞生物物理特性的互补专业知识汇聚在一起， PDAC细胞迁移和转移的机制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 正常胰腺他们假设，定义细胞身份的超级增强子相关基因， 是PDAC的有效治疗靶点。一个差异乙酰化的增强子区域被定位到 MICAL 2基因，编码黄素单加氧酶。这种蛋白质驱动F-肌动蛋白解聚， 胞质溶胶可以重构肌动蛋白肌球蛋白机制，用于迁移和响应外部机械和 生化信号MICAL 2还在连接核肌动蛋白动力学和血清反应因子中起作用。 (SRF)转录。肌心素相关转录因子（MTRFs）是SRF的共激活因子;当核 肌动蛋白解聚由MICAL 2诱导，球状肌动蛋白靶向核输出，释放MTRF， 结合SRF并激活对细胞粘附和迁移重要的基因的转录。PDAC细胞研究 表明沉默MICAL 2表达损害细胞迁移和转移。 卡蒂拉实验室与恩格勒博士的研究小组合作，报告说，细胞色素作为一种 转移潜能的生物物理标志物，并且收缩性和收缩性都使adurotaxis， 细胞迁移的能力，而不管刚度梯度。这个项目的目标是定义MICAL 2 影响了肿瘤和硬脊膜扩张的性质，以及它如何调节性质，不仅是癌症的性质， 细胞，但肿瘤微环境通过调节基因表达。我们假设MICAL 2 通过细胞自主性和非细胞自主性促进PDAC细胞的侵袭和转移 机制等我们将在三个具体目标中测试这一假设：1）确定MICAL 2如何调节 2）确定MICAL 2如何促进胰腺癌 细胞迁移和转移，以及3）确定MICAL 2如何与来自癌症基质细胞的信号传导相关 调节肿瘤微环境。作为一个假定的治疗靶点，我们的目标是确定MICAL 2 在PDAC进展过程中功能性调节细胞迁移和转移能力。这些知识将 了解MICAL 2活性如何以及何时可以在PDAC中靶向的关键。