权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Integrin Regulation of Non-apoptotic Death in Breast Cancer

整合素对乳腺癌非凋亡死亡的调节

基本信息

批准号：
10439666
负责人：
Arthur M Mercurio
金额：
$ 37.55万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-11 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439666
关键词：
Address Antioxidants Apoptosis Autophagocytosis Biology Blood Circulation Breast Breast Cancer Cell Breast Carcinoma Buffers Carcinoma Cell Death Cell Survival Cell membrane Cells Cessation of life Complex Cysteine Cystine Data Development Distant Extracellular Matrix F-Actin Glutamates Glutathione Growth Integrins Investigation Iron Lipid Peroxidation Lipid Peroxides Lipids Malignant Epithelial Cell Malignant Neoplasms Mediating Messenger RNA Methylation Mus Neoplasm Circulating Cells Neoplasm Metastasis Organ Peroxidases Process RNA Reactive Oxygen Species Regulation Resistance Role Signal Transduction Stress System Therapeutic Intervention Transgenic Mice Transgenic Model Tumor Biology antiporter breast tumorigenesis design effective therapy erastin glutathione peroxidase in vivo mRNA Stability malignant breast neoplasm mammary epithelium mouse model neoplastic cell novel novel therapeutic intervention prevent repair enzyme response therapy development triple-negative invasive breast carcinoma tumor initiation

项目摘要

Summary This proposal will examine the regulation and role of ferroptosis in epithelial and carcinoma biology. Ferroptosis involves the accumulation of intracellular reactive oxygen species (ROS) leading to inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the consequent increase in lipid peroxides that causes cell death. Data obtained reveal that extracellular matrix (ECM)-detached mammary epithelial and breast carcinoma cells undergo ferroptosis specifically in the absence of a6b4. Also, ECM-detached cells that cluster are prone to ferroptosis in the absence of a6b4. In contrast, single cells undergo apoptosis if a6b4 expression is depleted. The ability of a6b4 to signal an anti-ferroptotic response in ECM-detached cells appears to be dependent on F-actin-rich, cell-cell complexes and that a6b4 may nucleate the formation of these complexes, which have been termed ‘ferroptosis resistance complexes’. It is hypothesized that a6b4 signaling under these conditions buffers an increase in lipid peroxidation that occurs as a result of ECM detachment by maintaining the expression of GPX4, a lipid peroxidase, enabling the evasion of ferroptosis. It is proposed that the mechanism involves the ability of a6b4 signaling to stabilize GPX4 mRNA and prevents its decay in stress conditions by promoting N6-methyladenosine (m6A) RNA de-methylation. The first aim will investigate how a6b4 signaling is activated in ECM-detached cells and its role in the formation of ferroptosis resistance complexes. The second aim will determine that a6b4 signaling impacts the stability of GPX4 and other mRNAs in response to ECM-detachment. This aim will also involve identifying the spectrum of mRNAs that are stabilized by m6A-de-methylation upon ECM-detachment. The final aim will investigate the significance of a6b4 regulation of GPX4 and evasion of ferroptosis in breast cancer using mouse models. This aim will involve an unbiased approach to assessing the contribution of GPX4 to breast tumorigenesis and progression by conditional deletion in a transgenic mouse model of triple-negative breast cancer. Analysis of these mice will enable an assessment of the contribution of GPX4 to tumor initiation, growth and metastasis, including circulating tumor cells, and its role in the evasion of ferroptosis in vivo. The novel and unanticipated hypotheses to be addressed have the potential to open a new field of investigation with significant implications for our understanding of both ferroptosis and tumor biology that could benefit the design and development of therapies to impede metastasis. !

总结

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protocol for the separation of extracellular vesicles by ultracentrifugation from in vitro cell culture models.

DOI：
10.1016/j.xpro.2021.100303
发表时间：
2021-03-19
期刊：
STAR protocols
影响因子：
0
作者：
Chhoy P;Brown CW;Amante JJ;Mercurio AM
通讯作者：
Mercurio AM

Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export.

DOI：
10.1016/j.devcel.2019.10.007
发表时间：
2019-12-02
期刊：
Developmental cell
影响因子：
11.8
作者：
Brown CW;Amante JJ;Chhoy P;Elaimy AL;Liu H;Zhu LJ;Baer CE;Dixon SJ;Mercurio AM
通讯作者：
Mercurio AM

Targeting prominin2 transcription to overcome ferroptosis resistance in cancer.