Mitophagy-Mediated Cell Death in Mammary Tumorigenesis

乳腺肿瘤发生中线粒体自噬介导的细胞死亡

基本信息

  • 批准号:
    10470906
  • 负责人:
  • 金额:
    $ 39.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary Background: The metastasis of cancerous cells to distant and vital organs is responsible for in excess of 90% of cancer mortalities. Given this extraordinarily high mortality rate, there is a significant need for the development of novel therapeutic approaches that either eliminate metastatic cancer cells or eradicate incipient cancer cells prior to metastatic dissemination. An important barrier to tumor progression and metastasis is anoikis, a caspase- dependent cell death program induced by loss of integrin-mediated attachment to extracellular matrix (ECM). However, it has become clear that ECM-detachment can induce anoikis-independent mechanisms that can compromise cell viability. More specifically, we have discovered that detachment of non-cancerous epithelial cells from ECM triggers a significant elevation in the levels of reactive oxygen species (ROS) which compromises cell survival in an anoikis-independent fashion. The understanding of the cellular changes that contribute to the elevation of ROS during ECM-detachment remains rudimentary and the strategies utilized by cancer cells to combat ROS during ECM-detachment are insufficiently explored. Therefore, these points represent significant knowledge gaps that this grant proposal aims to address. Discernment of mechanistic information regarding the links between ECM-detachment, ROS, and cell survival could provide targets for the design of the therapeutic approaches aimed at specifically eliminating ECM-detached cancer cells; an outcome that may have significant impact for patients with metastatic disease. Objective/hypothesis: In aggregate, our preliminary studies have unveiled a novel cell death mechanism (with a tumor suppressive function) that compromises the viability of ECM-detached cells: the induction of mitophagy as consequence of RIPK1 signaling. As such, these data have motivated our central hypothesis that RIPK1- mediated mitophagy during ECM-detachment functions as a barrier to breast cancer progression. Specific Aim I: To elucidate the molecular mechanism by which ECM-detachment promotes RIPK1-dependent mitophagy and initiates cell death. Specific Aim II: To assess the capacity of RIPK1-mediated mitophagy to antagonize tumor formation in vivo and to evaluate antioxidant inhibition as a novel strategy to limit tumorigenesis in cancers that are deficient in RIPK1-mediated mitophagy Anticipated Outcomes: Following the completion of these studies, we will have accumulated significant mechanistic knowledge regarding the relationship between ECM-detachment, RIPK1 mitophagy, and cell death. Thus, the completion of these studies will unveil fundamental biological insights regarding cancer cell survival during ECM-detachment that may ultimately lead to the development of therapeutic approaches to limit the dissemination of breast cancer cells.
项目摘要 背景:癌细胞向远处和重要器官的转移占90%以上。 癌症死亡率。鉴于这一极高的死亡率,有很大的发展需要 新的治疗方法,要么消除转移的癌细胞,要么根除早期的癌细胞 在转移扩散之前。肿瘤进展和转移的一个重要障碍是失巢凋亡,这是一种半胱氨酸氨基转移酶- 由于失去整合素介导的与细胞外基质(ECM)的附着而导致依赖的细胞死亡程序。 然而,已清楚的是,细胞外基质脱离可以诱导失巢细胞非依赖性机制,从而 损害细胞的生存能力。更具体地说,我们发现非癌上皮的脱落 来自ECM的细胞触发活性氧物种(ROS)水平的显著升高,从而损害 细胞以失巢无核细胞独立的方式存活。对细胞变化的理解有助于 在ECM脱离过程中ROS的升高仍然是初步的,癌细胞利用的策略是 ECM-支队中的作战RO还没有得到充分的探索。因此,这些观点具有重要意义 这项赠款提案旨在解决的知识差距。关于机械信息的识别 细胞外基质脱离、ROS和细胞存活之间的联系可以为治疗的设计提供靶点。 旨在具体消除ECM分离的癌细胞的方法;这一结果可能具有重要意义 对转移性疾病患者的影响。 目标/假设:总的来说,我们的初步研究揭示了一种新的细胞死亡机制(与 肿瘤抑制功能)损害细胞外基质分离细胞的活性:诱导有丝分裂 作为RIPK1信令的结果。因此,这些数据激发了我们的核心假设,即RIPK1- 细胞外基质脱离过程中介导的丝裂原吞噬作用是乳腺癌进展的障碍。 特异性目的I:阐明细胞外基质脱离促进RIPK1依赖的分子机制 有丝分裂并引发细胞死亡。 特定目的II:评价RIPK1介导的有丝分裂噬菌体体内抗肿瘤形成的能力 并评估抗氧化抑制作为一种新的策略来限制缺乏抗氧化剂的癌症的肿瘤形成 RIPK1介导的有丝分裂吞噬作用 预期结果:在这些研究完成后,我们将积累大量 关于细胞外基质脱离、RIPK1有丝分裂和细胞死亡之间关系的机械知识。 因此,这些研究的完成将揭示有关癌细胞的基本生物学见解。 ECM-脱离期间的存活最终可能导致治疗方法的发展 以限制乳腺癌细胞的扩散。

项目成果

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Zachary T. Schafer其他文献

Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression
癌细胞在脱离细胞外基质期间的存活:肿瘤进展的多重障碍
  • DOI:
    10.1038/nrc3789
  • 发表时间:
    2014-08-07
  • 期刊:
  • 影响因子:
    66.800
  • 作者:
    Cassandra L. Buchheit;Kelsey J. Weigel;Zachary T. Schafer
  • 通讯作者:
    Zachary T. Schafer
Ancestry-linked stromal variations impact breast epithelial cell invasion
与祖先相关的基质变异影响乳腺上皮细胞侵袭
  • DOI:
    10.1016/j.isci.2025.112686
  • 发表时间:
    2025-06-20
  • 期刊:
  • 影响因子:
    4.100
  • 作者:
    Madison G. Schmidtmann;Victoria Elliott;James W. Clancy;Zachary T. Schafer;Harikrishna Nakshatri;Crislyn D’Souza-Schorey
  • 通讯作者:
    Crislyn D’Souza-Schorey

Zachary T. Schafer的其他文献

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{{ truncateString('Zachary T. Schafer', 18)}}的其他基金

Mitophagy-Mediated Cell Death in Mammary Tumorigenesis
乳腺肿瘤发生中线粒体自噬介导的细胞死亡
  • 批准号:
    10277900
  • 财政年份:
    2021
  • 资助金额:
    $ 39.06万
  • 项目类别:
The Role of Metabolic Alterations in Anchorage-Independent Survival
代谢改变在锚地独立生存中的作用
  • 批准号:
    7484234
  • 财政年份:
    2007
  • 资助金额:
    $ 39.06万
  • 项目类别:
The Role of Metabolic Alterations in Anchorage-Independent Survival
代谢改变在锚地独立生存中的作用
  • 批准号:
    7328792
  • 财政年份:
    2007
  • 资助金额:
    $ 39.06万
  • 项目类别:

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