Intersection of autophagy and vesicle trafficking in Her2-positive breast cancer

Her2 阳性乳腺癌中自噬和囊泡运输的交叉点

基本信息

  • 批准号:
    10658423
  • 负责人:
  • 金额:
    $ 40.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-13 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

Breast cancer is the most common malignancy among US women and remains a major health threat with high incidence and lethality due to therapeutic resistance and metastasis. Breast cancer is also a heterogenous disease with different subtypes, including HER2+ subtype accounting for about 25% of patients. Despite the remarkable progress in recent years including anti-HER2 targeted therapy, our understanding of the mechanistic basis for breast cancer, particularly metastasis is still very limited. The long-term goal of the proposed studies is to understand the molecular and cellular mechanisms of metastasis and therapeutic resistance of HER2+ and other breast cancers that are ultimately responsible for patient lethality. In the prior funding period, we generated and analyzed mouse models for HER2+ breast cancer with deletion of an essential autophagy gene FIP200 or Fip200-4A mutation specifically blocking its autophagy activity and discovered that blocking FIP200-mediated autophagy abolished mammary tumorigenesis and metastasis through a new mechanism directly regulating the oncogenic driver HER2 itself. We showed that autophagy blockade abolishes mammary tumorigenesis and metastasis by decreasing levels of HER2 on the plasma membrane of mouse and human tumor cells due to aberrant HER2 trafficking from the Golgi to endosomes and multiple vesicular bodies (MVBs) and eventually released from tumor cells in small extracellular vesicles (sEVs). Additionally, employing single-cell RNA sequencing (scRNA-seq) and bioinformatics analysis, we developed a workflow to determine pharmacological interventions that would yield similar effects as FIP200 ablation. We also found FIP200 acetylation at K276 by CBP that regulates its stability. Lastly, we performed an in vivo CRISPR-Cas9 screen of a custom designed library of autophagy regulatory genes using our unique HER2+ mammary tumor cells and identified p47 as a putative suppressor for HER2+ breast cancer metastasis. Previous studies showed a role for p47 in regulating membrane fusion events, autophagy, and NFκB signaling, suggesting potential crosstalk between autophagy with vesicle trafficking in breast cancer metastasis. Based on these strong preliminary data and using our unique mouse and cell models, we propose to 1) determine the mechanism of autophagy regulation of HER2 trafficking in mouse and human breast cancer cells, 2) identify pharmacological agents that can disrupt the functions of FIP200 in mouse and human breast cancer cells as well as patient-derived models, and 3) explore the role and mechanisms of regulation of HER2+ breast cancer metastasis by p47. Together, these studies will provide significant insights into the molecular and cellular mechanisms of breast cancer metastasis that may contribute to novel therapies for this devastating disease.
乳腺癌是美国女性最常见的恶性肿瘤,并且仍然是一个主要的健康威胁 由于治疗耐药和转移而导致高发病率和致死率。乳腺癌也是一种异质性癌症 疾病有不同亚型,其中HER2+亚型约占患者的25%。尽管 近年来,包括抗 HER2 靶向治疗在内的显着进展,我们对其机制的了解 乳腺癌的基础,特别是转移的基础仍然非常有限。拟议研究的长期目标是 了解 HER2+ 和治疗耐药的分子和细胞机制 最终导致患者死亡的其他乳腺癌。在之前的资助期间,我们产生了 并分析了缺失必需自噬基因 FIP200 的 HER2+ 乳腺癌小鼠模型或 Fip200-4A突变特异性阻断其自噬活性,并发现阻断FIP200介导的自噬活性 自噬通过直接调节乳腺肿瘤的新机制消除了乳腺肿瘤的发生和转移 致癌驱动程序 HER2 本身。我们发现自噬阻断可以消除​​乳腺肿瘤的发生 通过降低小鼠和人类肿瘤细胞质膜上的 HER2 水平来促进转移 异常的 HER2 从高尔基体运输到内体和多个囊泡体 (MVB),并最终 由小细胞外囊泡 (sEV) 中的肿瘤细胞释放。此外,利用单细胞 RNA 测序(scRNA-seq)和生物信息学分析,我们开发了一个工作流程来确定药理学 干预措施将产生与 FIP200 消融类似的效果。我们还发现 FIP200 在 K276 处乙酰化 CBP 负责调节其稳定性。最后,我们对定制设计的 CRISPR-Cas9 进行了体内筛选 使用我们独特的 HER2+ 乳腺肿瘤细胞构建自噬调节基因库,并将 p47 鉴定为 HER2+ 乳腺癌转移的假定抑制剂。先前的研究表明 p47 在调节中发挥作用 膜融合事件、自噬和 NFκB 信号传导,表明自噬之间存在潜在的串扰 乳腺癌转移中的囊泡贩运。基于这些强有力的初步数据并使用我们独特的 小鼠和细胞模型,我们建议 1) 确定 HER2 运输的自噬调节机制 在小鼠和人类乳腺癌细胞中,2) 鉴定出可以破坏细胞功能的药物 FIP200 在小鼠和人类乳腺癌细胞以及患者衍生模型中的作用,以及 3) 探索其作用和 p47 调节 HER2+ 乳腺癌转移的机制。这些研究将共同​​提供 对乳腺癌转移的分子和细胞机制的重要见解可能有助于 针对这种毁灭性疾病的新疗法。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Breast Cancer: Multiple Subtypes within a Tumor?
  • DOI:
    10.1016/j.trecan.2017.09.001
  • 发表时间:
    2017-11
  • 期刊:
  • 影响因子:
    18.4
  • 作者:
    Yeo SK;Guan JL
  • 通讯作者:
    Guan JL
Autophagy inhibition perturbs ERBB2 trafficking and abolishes tumorigenesis in ERBB2-driven breast cancer.
自噬抑制扰乱 ERBB2 运输并消除 ERBB2 驱动的乳腺癌中的肿瘤发生。
  • DOI:
    10.1080/15548627.2021.1907168
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    13.3
  • 作者:
    Hao,Mingang;Yeo,SynKok;Guan,Jun-Lin
  • 通讯作者:
    Guan,Jun-Lin
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JUN-LIN GUAN其他文献

JUN-LIN GUAN的其他文献

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{{ truncateString('JUN-LIN GUAN', 18)}}的其他基金

Mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions
FIP200通过自噬和非自噬功能调控乳腺癌的机制
  • 批准号:
    10166785
  • 财政年份:
    2017
  • 资助金额:
    $ 40.76万
  • 项目类别:
Mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions
FIP200通过自噬和非自噬功能调控乳腺癌的机制
  • 批准号:
    9927485
  • 财政年份:
    2017
  • 资助金额:
    $ 40.76万
  • 项目类别:
Mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions
FIP200通过自噬和非自噬功能调控乳腺癌的机制
  • 批准号:
    9381905
  • 财政年份:
    2017
  • 资助金额:
    $ 40.76万
  • 项目类别:
Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes
自噬基因对神经干细胞和神经发生的调节
  • 批准号:
    10221784
  • 财政年份:
    2015
  • 资助金额:
    $ 40.76万
  • 项目类别:
Mechanisms of Neural Stem Cells Regulation by Autophagy
自噬调节神经干细胞的机制
  • 批准号:
    9001627
  • 财政年份:
    2015
  • 资助金额:
    $ 40.76万
  • 项目类别:
Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes
自噬基因对神经干细胞和神经发生的调节
  • 批准号:
    10434019
  • 财政年份:
    2015
  • 资助金额:
    $ 40.76万
  • 项目类别:
Regulation of neural stem cells and neurogenesis by autophagy genes
自噬基因调控神经干细胞和神经发生
  • 批准号:
    10047559
  • 财政年份:
    2015
  • 资助金额:
    $ 40.76万
  • 项目类别:
Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes
自噬基因对神经干细胞和神经发生的调节
  • 批准号:
    10673701
  • 财政年份:
    2015
  • 资助金额:
    $ 40.76万
  • 项目类别:
Genetic Analysis of FAK kinase and scaffold functions in breast cancer
乳腺癌中 FAK 激酶和支架功能的遗传分析
  • 批准号:
    8477152
  • 财政年份:
    2012
  • 资助金额:
    $ 40.76万
  • 项目类别:
Genetic Analysis of FAK kinase and scaffold functions in breast cancer
乳腺癌中 FAK 激酶和支架功能的遗传分析
  • 批准号:
    8907919
  • 财政年份:
    2012
  • 资助金额:
    $ 40.76万
  • 项目类别:

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