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:
    10521975
  • 负责人:
  • 金额:
    $ 6.99万
  • 依托单位:
  • 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:
    2020-05-01 至 2025-02-28
  • 项目状态:
    未结题

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Lauren Elizabeth Ball其他文献

Lauren Elizabeth Ball的其他文献

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{{ truncateString('Lauren Elizabeth Ball', 18)}}的其他基金

Proteomics Core
蛋白质组学核心
  • 批准号:
    10460362
  • 财政年份:
    2021
  • 资助金额:
    $ 6.99万
  • 项目类别:
Quadrupole Orbitrap Hybrid Mass Spectrometer for Proteomics
用于蛋白质组学的四极 Orbitrap 混合质谱仪
  • 批准号:
    10177354
  • 财政年份:
    2021
  • 资助金额:
    $ 6.99万
  • 项目类别:
Proteomics Core
蛋白质组学核心
  • 批准号:
    10674960
  • 财政年份:
    2021
  • 资助金额:
    $ 6.99万
  • 项目类别:
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:
    10574514
  • 财政年份:
    2020
  • 资助金额:
    $ 6.99万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 6.99万
  • 项目类别:
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:
    10349546
  • 财政年份:
    2020
  • 资助金额:
    $ 6.99万
  • 项目类别:
Orbitrap Mass Spectrometer
Orbitrap 质谱仪
  • 批准号:
    8247428
  • 财政年份:
    2012
  • 资助金额:
    $ 6.99万
  • 项目类别:
Proteomics Core
蛋白质组学核心
  • 批准号:
    10005398
  • 财政年份:
    2011
  • 资助金额:
    $ 6.99万
  • 项目类别:
COBRE P3: ROLE OF HEXOSAMINE BIOSYNTHETIC PATHWAY AND POSTRANSLATIONAL O-GLCNAC
COBRE P3:己糖胺生物合成途径和翻译后 O-GLNAC 的作用
  • 批准号:
    8167765
  • 财政年份:
    2010
  • 资助金额:
    $ 6.99万
  • 项目类别:
Regulation of IGF-1 and Insulin Signaling by O-GlcNAc Glycosylation
O-GlcNAc 糖基化对 IGF-1 和胰岛素信号传导的调节
  • 批准号:
    8279112
  • 财政年份:
    2010
  • 资助金额:
    $ 6.99万
  • 项目类别:

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