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. !

概括该提案将检查铁凋亡在上皮和癌生物学中的调节和作用。铁凋亡涉及细胞内活性氧（ROS）的积累，导致失活脂质修复酶谷胱甘肽过氧化物酶4（GPX4）以及随之而来的脂质过氧化物的增加导致细胞死亡。获得的数据表明，细胞外基质（ECM）可以解决的乳腺上皮和在没有A6B4的情况下，乳腺癌细胞专门发生铁铁病。此外，ECM详细的细胞在没有A6B4的情况下，簇容易发生铁毒。相反，如果A6B4，单细胞会经历凋亡表达耗尽。 A6B4在ECM触及的细胞中向抗肿瘤反应发出信号的能力似乎取决于富含F-肌动蛋白，细胞 - 细胞复合物，A6B4可能会核形成这些复合物被称为“耐铁抗性抗性复合物”。假设A6B4 在这些条件下的信号传导缓冲脂质过氧化导致ECM导致的脂质过氧化的增加通过维持脂质过氧化物酶GPX4的表达来脱离，从而能够进化的铁氧化。它提出该机制涉及A6B4信号稳定GPX4 mRNA的能力并防止其通过促进N6-甲基趋化（M6A）RNA脱甲基化，在应力条件下衰减。第一个目标研究如何在ECM触及的细胞中激活A6B4信号及其在铁凋亡形成中的作用电阻络合物。第二个目标将确定A6B4信号传导会影响GPX4和其他mRNA响应ECM核能。此目标还将涉及识别mRNA的光谱 ECM脱节后通过M6A-DE-甲基化稳定。最终目标将调查重要性使用小鼠模型，乳腺癌中GPX4的A6B4调节和铁腐病的演变。这个目标涉及一种评估GPX4对乳腺肿瘤发生和进展的贡献的无偏方法通过三阴性乳腺癌的转基因小鼠模型中的条件缺失。这些小鼠的分析将对GPX4对肿瘤起始，生长和转移的贡献进行评估，包括循环肿瘤细胞，及其在体内繁殖的作用中的作用。小说和意外的要解决的假设有可能开设一个新的投资领域，具有重大影响为了了解可能有利于设计和开发的铁铁作用和肿瘤生物学阻碍转移的疗法。呢

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

Targeting prominin2 transcription to overcome ferroptosis resistance in cancer.

DOI：
10.15252/emmm.202013792
发表时间：
2021-08-09
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Brown CW;Chhoy P;Mukhopadhyay D;Karner ER;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