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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.

项目总结