Role of O-GlcNAcome on Breast Cancer Initiating Cells

O-GlcNAcome 对乳腺癌起始细胞的作用

• 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
• 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

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.

项目摘要 人们普遍认为肿瘤是高度异质性的。肿瘤中细胞的亚群， 称为肿瘤发射细胞，可以隔离并能够自我更新，区分和形成大部分 瘤。许多癌症对传统的化疗或放射疗法没有反应，而那些最初的癌症 反应，经常复发。常规疗法仅攻击增殖细胞，留下耐药池 能够再生整个肿瘤的干细胞。了解调节肿瘤的机制 发起活动将导致设计和开发有效的治疗剂。我们的实验室已经证明了 第一次，营养传感器O-GLCNAC转移酶（OGT）在体外和IN调节癌症引发细胞 体内。从遗传或药理上减少OGT，在体外阻断乳腺圈形成并减少 上皮 - 间质标记（EMT），癌症干细胞标记。重要的是，OGT的过表达 多个乳腺癌细胞增加了包括纳米在内的癌症干细胞标记，增加了乳腺 体外形成并增加体内肿瘤起始。在此提案中，我们希望发现分子 OGT通过部分理解OGT相互作用组和O-来调节肿瘤起始的机制 乳腺癌肿瘤引发细胞的Glcnacome。这些信息将使我们能够识别新颖的治疗性 治疗癌症和反向耐药性的靶标。基于我们的初步结果，中央假设 该应用的是，营养传感器O-GLCNAC转移酶在乳腺癌中起着基本作用 通过纳米调节启动细胞。这些实验的完成将有助于我们 了解营养感应途径如何在分子水平上连接到自我更新的癌症茎 细胞（CSC），并提供一个框架，以了解代谢途径的癌症如何改变 调节控制CSC维护的核心自我更新信号。在AIM＃1中，我们将确定 OGT/O-GLCNAC调节的分子基础，主管纳米。这个目标将决定 乳腺癌肿瘤启动细胞中Nanog的OGT调节的分子基础。在AIM＃2中，我们将确定 OGT在癌细胞与癌细胞之间之间的相互作用组/O-Glcnacome。这个目标将确定 OGT相互作用的蛋白质和O-Glcnacylated蛋白在肿瘤中引发细胞，以鉴定新的途径和 肿瘤发射能力的调节剂。最终目标将评估OGT在调节肿瘤发射中的作用 体内活动。重要的是，我们将测试临床前癌模型中的新型OGT抑制剂，并测试是否是否 OGT靶向药物作为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。这些研究将进一步了解癌症的代谢重新编程 细胞在分子水平上连接到引发细胞的肿瘤，并将对 营养传感器OGT可以将癌症的起始途径融为一体，并确定OGT作为治疗靶标的 抗性癌的治疗。