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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. !

概括该提案将研究铁死亡在上皮和癌症生物学中的调节和作用。铁死亡涉及细胞内活性氧 (ROS) 的积累，导致细胞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）分离的乳腺上皮和乳腺癌细胞在缺乏 a6b4 的情况下会发生铁死亡。此外，ECM 分离的细胞在缺乏 a6b4 的情况下，簇容易发生铁死亡。相反，如果a6b4，单细胞会发生凋亡表达已耗尽。 a6b4 在 ECM 分离细胞中发出抗铁死亡反应的能力似乎依赖于富含 F-肌动蛋白的细胞-细胞复合物，并且 a6b4 可能使这些复合物被称为“铁死亡抗性复合物”。假设 a6b4 这些条件下的信号传导可缓冲 ECM 导致的脂质过氧化的增加通过维持 GPX4（一种脂质过氧化物酶）的表达来实现脱离，从而避免铁死亡。它据推测，该机制涉及 a6b4 信号传导稳定 GPX4 mRNA 并防止其发生的能力。通过促进 N6-甲基腺苷 (m6A) RNA 去甲基化来减弱应激条件。第一个目标将研究a6b4信号如何在ECM分离细胞中被激活及其在铁死亡形成中的作用抵抗复合物。第二个目标将确定 a6b4 信号传导影响 GPX4 的稳定性和其他响应 ECM 分离的 mRNA。这一目标还涉及鉴定 mRNA 谱 ECM 分离后通过 m6A 去甲基化来稳定。最终目的将探讨意义使用小鼠模型研究乳腺癌中 a6b4 对 GPX4 的调节和铁死亡的逃避。这一目标将涉及一种公正的方法来评估 GPX4 对乳腺肿瘤发生和进展的贡献通过在三阴性乳腺癌转基因小鼠模型中进行条件删除。对这些小鼠的分析将能够评估 GPX4 对肿瘤发生、生长和转移的贡献，包括循环肿瘤细胞及其在体内逃避铁死亡中的作用。新颖且出乎意料要解决的假设有可能开辟一个具有重大影响的新研究领域促进我们对铁死亡和肿瘤生物学的理解，这可能有利于设计和开发阻止转移的疗法。！

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