Role of O-GlcNAcome on Breast Cancer Initiating Cells

O-GlcNAcome 对乳腺癌起始细胞的作用

基本信息

批准号：
10737851
负责人：
Lauren Elizabeth Ball
金额：
$ 7.66万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737851
关键词：
Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast Epithelial Cells Cancer Control Cancer Model Cell Death Cell Maintenance Cell Proliferation Cells Data Disease Drug Targeting Drug resistance Enzymes Epithelium Gene Expression Regulation Glucose Glutamine Glycolysis Goals Grant Growth Hexosamines In Vitro Link Malignant Neoplasms Mammospheres Metabolic Metabolic Pathway Metabolism Molecular Natural regeneration Neoplasm Metastasis Nuclear Nutrient O-GlcNAc transferase Oxygen Pathway interactions Phenotype Play Process Property Proteins Radiation therapy Regulation Relapse Resistance Role Shunt Device Signal Transduction Stem Cell Factor Testing Therapeutic Time cancer cell cancer initiation cancer stem cell cancer therapy chemotherapy conventional therapy design detection of nutrient endoplasmic reticulum stress experimental study glycosylation in vivo in vivo Model inhibitor malignant breast neoplasm new therapeutic target novel overexpression pharmacologic pre-clinical prostate cancer cell rapid growth refractory cancer self-renewal sensor stem cell biomarkers stem-like cell therapeutic target therapeutically effective tumor tumor growth tumor initiation

项目摘要

Project Summary It is widely accepted that tumors are highly heterogeneous. There is a subpopulation of cells in a tumor, called tumor-initiating cell, that can be isolated and are able to self-renew, differentiate and form the bulk of the tumor. Many cancers don't respond to traditional chemotherapy or radiotherapy, and those that initially respond, often relapse. Conventional therapy only attacks proliferating cells, leaving behind a pool of resistant stem-like cells that are able to regenerate the whole tumor. Understanding mechanisms that regulate tumor- initiating activity will lead to designing and developing effective therapeutics. Our lab has demonstrated for the first time that the nutrient sensor O-GlcNAc transferase (OGT) regulates cancer-initiating cells in vitro and in vivo. Reducing OGT, genetically or pharmacologically, blocks mammosphere formation in vitro and reduced epithelial-mesechymal markers (EMT), cancer stem cell markers. Importantly, overexpression of OGT, in multiple breast cancer cells, increases cancer stem cell markers including NANOG, increases mammosphere formation in vitro and increases tumor initiation in vivo. In this proposal, we hope to uncover molecular mechanism by which OGT regulates tumor initiation, by in part, understanding OGT interactome and O- GlcNAcome in breast cancer tumor initiating cells. This information will allow us to identify novel therapeutic targets in treating cancer and reverse drug resistance. Based on our preliminary results, the central hypothesis of this application is that the nutrient sensor O-GlcNAc transferase plays a fundamental role in breast cancer initiating cells via, in part, NANOG regulation. Completion of these experiments will contribute to our understanding of how nutrient-sensing pathways connects at the molecular level to self-renewing cancer stem cells (CSCs) and providing a framework for understanding how cancer alterations in metabolic pathways regulate core self-renewal signaling that controls CSC maintenance. In Aim #1, we will determine the molecular basis of OGT/O-GlcNAc regulation of the master CSC regulator NANOG. This aim will determine the molecular basis of OGT regulation of NANOG in breast cancer tumor initiating cells. In Aim #2, we will Identify OGT interactome/O-GlcNAcome between between cancer cells and cancer stem cells. This aim will identify OGT interacting proteins and O-GlcNAcylated protein in tumor initiating cells to identify novel pathways and regulators of tumor-initiating ability. The final aim will evaluate the role of OGT in regulating tumor-initiating activity in vivo. Importantly, we will test novel OGT inhibitors in preclinical cancer models and test whether OGT targeting drugs as potential anti-tumor initiation cell therapeutic strategy against breast cancer growth and metastasis in vivo. These studies will further our understanding of how metabolic reprogramming in cancer cells connects at the molecular level to tumor initiating cells and will create mechanistic understanding of how nutrient sensor OGT can couple to cancer initiation pathways and establish OGT as therapeutic target for treatment of resistant cancers.

项目概要人们普遍认为肿瘤具有高度异质性。肿瘤中有一个细胞亚群，称为肿瘤起始细胞，可以分离并能够自我更新、分化并形成肿瘤的大部分瘤。许多癌症对传统的化疗或放疗没有反应，而那些最初的癌症反应，经常复发。传统疗法仅攻击增殖细胞，留下大量耐药细胞能够再生整个肿瘤的干细胞样细胞。了解调节肿瘤的机制发起活动将导致设计和开发有效的疗法。我们的实验室已经证明了营养传感器 O-GlcNAc 转移酶 (OGT) 首次在体外和体内调节癌症起始细胞体内。通过遗传或药理学方法减少 OGT，可阻止体外乳腺球的形成并减少上皮间充质标记物（EMT）、癌症干细胞标记物。重要的是，OGT 的过度表达多个乳腺癌细胞，增加癌症干细胞标记物，包括 NANOG，增加乳腺球体外形成并增加体内肿瘤的发生。在这个提案中，我们希望揭示分子 OGT 调节肿瘤发生的机制，部分通过了解 OGT 相互作用组和 O- GlcNA 出现在乳腺癌肿瘤起始细胞中。这些信息将使我们能够确定新的治疗方法治疗癌症和逆转耐药性的目标。根据我们的初步结果，中心假设该应用的核心在于营养传感器 O-GlcNAc 转移酶在乳腺癌中发挥着重要作用部分通过 NANOG 调节启动细胞。完成这些实验将有助于我们了解营养感应途径如何在分子水平上与自我更新的癌症干细胞连接细胞（CSC）并提供一个框架来了解癌症如何改变代谢途径调节控制 CSC 维护的核心自我更新信号。在目标#1中，我们将确定 OGT/O-GlcNAc 对 CSC 主调节器 NANOG 调节的分子基础。这个目标将决定乳腺癌肿瘤起始细胞中 NANOG 的 OGT 调节的分子基础。在目标 2 中，我们将确定 OGT 相互作用组/O-GlcNA 介于癌细胞和癌症干细胞之间。这一目标将确定肿瘤起始细胞中的 OGT 相互作用蛋白和 O-GlcNAc 酰化蛋白可识别新途径并肿瘤启动能力的调节因子。最终目标是评估OGT在调节肿瘤发生中的作用体内活性。重要的是，我们将在临床前癌症模型中测试新型 OGT 抑制剂，并测试是否 OGT靶向药物作为对抗乳腺癌生长的潜在抗肿瘤起始细胞治疗策略和体内转移。这些研究将进一步加深我们对癌症中代谢重编程的理解细胞在分子水平上与肿瘤起始细胞连接，并将产生关于如何产生机制的理解营养传感器 OGT 可以与癌症起始途径结合，并将 OGT 作为癌症的治疗靶点治疗耐药癌症。