Determinants of Liver Metastasis

肝转移的决定因素

基本信息

  • 批准号:
    10295701
  • 负责人:
  • 金额:
    $ 11.75万
  • 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:
    2021-03-01 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract. Non-alcoholic fatty liver disease can make the liver permissive to liver metastasis. Patients taking an androgen signaling inhibitor, such as enzalutamide for the treatment of prostate cancer can experience similar biologic changes to the liver. These systemic changes in the patient lipid profile are associated with liver injury can result in a quantifiable acceleration of biologic aging of the liver tissue. Prostate cancer cells acquire genetic adaptations that enable survival in the liver as a metastatic niche. We found that enzalutamide exposure promoted expression of BMP ligands in prostate cancer epithelial cells in a glutamine signaling-dependent manner. Enzalutamide also increased expression of SLC1A5, a glutamine transporter able to regulate tumor growth. Prostate cancer epithelial cells grown without glutamine had significantly lower levels of BMP ligands compared to cells treated with glutamine, glutamate or enzalutamide. Glutamine inhibition was found to block expression of SLC1A5 in prostate epithelia co-cultured with prostate cancer-associated fibroblasts. The mechanism of transporting glutamine into the epithelial cells was sufficiently blocked using these inhibitors, and fibroblast-specific genes were also affected. Wnt3a expression and glutamine secretion in prostate cancer- associated fibroblasts increased after enzalutamide but decreased with glutamine inhibition. Based on these novel findings, we tested if glutamine inhibition could be effective on the prostate tumor microenvironment, where prostate cancer epithelia and cancer-associated fibroblasts were co-cultured. We found that enzalutamide increased neuroendocrine differentiation in prostate epithelia, abrogated when co-cultures were treated with glutamine inhibitor alone or in combination with enzalutamide. The potential role of enzalutamide on methylation markers associated with biologic aging was observed where prostate epithelia treated with enzalutamide had increased promoter enrichment of TET2 on its downstream target TBX2; glutamine inhibition decreased promoter enrichment. We hypothesize that biologic aging of the liver induced by high fat diet impacts the hepatic microenvironment to permit prostate metastasis. In Aim 1, we will define epigenetic changes in the liver that occur as a result of androgen signaling inhibition using enzalutamide. We will determine how high fat diet influences methylation patterns in the liver in a tumor-free environment. In Aim 2, we will identify the role of biologic aging in the liver induced by high fat diet or enzalutamide treatment after primary tumor expansion occurs. We found that prostate cancer epithelial expression of TET2, a methylcytosine dioxygenase mutated in cancers, is increased with enzalutamide or glutamine treatments. We will explore the androgen-TET2 crosstalk in prostate cancer epithelia as an adaptation promoting liver metastasis. The mechanism by which high fat diet and liver aging contribute to prostate cancer metastasis to the liver will be studied.
项目概要/摘要。 非酒精性脂肪性肝病可使肝脏对肝转移具有宽容性。服用雄激素的患者 信号传导抑制剂,如用于治疗前列腺癌的恩杂鲁胺可以经历类似的生物学效应。 肝脏的变化。患者血脂谱的这些全身性变化与肝损伤相关, 在肝脏组织的生物老化的可量化的加速。前列腺癌细胞获得遗传 适应,使生存在肝脏作为一个转移的小生境。我们发现Enzalutamide暴露 促进前列腺癌上皮细胞中BMP配体的表达, 方式Enzalutamide还增加了SLC 1A 5的表达,SLC 1A 5是一种谷氨酰胺转运蛋白,能够调节肿瘤 增长在没有谷氨酰胺的情况下生长的前列腺癌上皮细胞的BMP配体水平显著降低 与用谷氨酰胺、谷氨酸盐或恩杂鲁胺处理的细胞相比。谷氨酰胺抑制被发现阻断 SLC 1A 5在与前列腺癌相关成纤维细胞共培养的前列腺上皮中的表达。的 使用这些抑制剂充分阻断了谷氨酰胺转运到上皮细胞中的机制, 成纤维细胞特异性基因也受到影响。前列腺癌中Wnt 3a表达和谷氨酰胺分泌 Enzalutamide后相关成纤维细胞增加,但谷氨酰胺抑制后减少。基于这些 新的发现,我们测试了谷氨酰胺抑制是否对前列腺肿瘤微环境有效, 将前列腺癌上皮细胞和癌症相关的成纤维细胞共培养。我们发现恩杂鲁胺 前列腺上皮细胞中神经内分泌分化增加,当共培养物用 谷氨酰胺抑制剂单独或与恩杂鲁胺组合。Enzalutamide对甲基化的潜在作用 在Enzalutamide治疗的前列腺上皮细胞中观察到与生物老化相关的标志物, TET 2在其下游靶标TBX 2上的启动子富集增加;谷氨酰胺抑制降低 启动子富集我们假设高脂饮食引起的肝脏生物老化影响了肝脏 微环境允许前列腺转移。在目标1中,我们将定义肝脏中的表观遗传变化, 由于使用enzalutamide抑制雄激素信号传导而发生。我们将确定如何高脂肪饮食 影响无肿瘤环境中肝脏的甲基化模式。在目标2中,我们将确定 原发性肿瘤扩大后高脂饮食或Enzalutamide治疗诱导的肝脏生物老化 发生。我们发现前列腺癌上皮细胞TET 2的表达,TET 2是一种甲基胞嘧啶双加氧酶突变, 癌症,随着恩杂鲁胺或谷氨酰胺治疗增加。我们将探索雄激素-TET 2串扰 在前列腺癌上皮中作为促进肝转移的适应。高脂肪饮食的机制 和肝脏老化有助于前列腺癌转移到肝脏将被研究。

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Neil A. Bhowmick其他文献

First-line Immune Checkpoint Inhibitor Combinations in Metastatic Renal Cell Carcinoma: Where Are We Going, Where Have We Been?
  • DOI:
    10.1007/s40265-022-01683-6
  • 发表时间:
    2022-02-17
  • 期刊:
  • 影响因子:
    14.400
  • 作者:
    Jacob J. Adashek;Joshua J. Breunig;Edwin Posadas;Neil A. Bhowmick;Leigh Ellis;Stephen J. Freedland;Hyung Kim;Robert Figlin;Jun Gong
  • 通讯作者:
    Jun Gong
603: Prostate Androgen Responsiveness Involve Stromal Transforming Growth Factor-Beta Signaling
  • DOI:
    10.1016/s0022-5347(18)37865-0
  • 发表时间:
    2004-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Neil A. Bhowmick;Susan Kasper
  • 通讯作者:
    Susan Kasper
413: The Conditional Knock-Out of Transforming Growth Factor-Beta Signaling in the Prostate Stroma Results in Prostate Intraepithelial Neoplasia
  • DOI:
    10.1016/s0022-5347(18)37675-4
  • 发表时间:
    2004-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Neil A. Bhowmick;Harold L. Moses
  • 通讯作者:
    Harold L. Moses
CD105 blockade restores osimertinib sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer
CD105阻断可恢复耐药的表皮生长因子受体(EGFR)突变型非小细胞肺癌对奥希替尼的敏感性
  • DOI:
    10.1016/j.drup.2025.101237
  • 发表时间:
    2025-07-01
  • 期刊:
  • 影响因子:
    21.700
  • 作者:
    Manish Thiruvalluvan;Sandrine Billet;Zhenqiu Liu;Joseph Lownik;Barliz Waissengrin;Hyoyoung Kim;Anton L. Villamejor;Larry Milshteyn;Xiamo Li;Matthew Gayhart;Manuel Araña;Kamya Sankar;Edwin M. Posadas;Jean Lopategui;Sungyong You;Karen L. Reckamp;Neil A. Bhowmick
  • 通讯作者:
    Neil A. Bhowmick
171: Expression of Dominant Active Transforming Growth Factor-Beta Receptor in Fetal Rat Bladder Stromal Cells
  • DOI:
    10.1016/s0022-5347(18)37433-0
  • 发表时间:
    2004-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jeffrey M. Donohoe;John C. Pope;Neil A. Bhowmick;Mark C. Adams;John W. Brock;Simon W. Hayward
  • 通讯作者:
    Simon W. Hayward

Neil A. Bhowmick的其他文献

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{{ truncateString('Neil A. Bhowmick', 18)}}的其他基金

Determinants of Liver Metastasis
肝转移的决定因素
  • 批准号:
    10701208
  • 财政年份:
    2022
  • 资助金额:
    $ 11.75万
  • 项目类别:
Determinants of Liver Metastasis
肝转移的决定因素
  • 批准号:
    10524071
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
Project 1- Role of fat in metastatic engraftment and expansion in the liver
项目 1 - 脂肪在肝脏转移植入和扩张中的作用
  • 批准号:
    10807146
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
Project 1- Role of fat in metastatic engraftment and expansion in the liver
项目 1 - 脂肪在肝脏转移植入和扩张中的作用
  • 批准号:
    10558474
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
Determinants of Liver Metastasis
肝转移的决定因素
  • 批准号:
    10558473
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
Project 1- Role of fat in metastatic engraftment and expansion in the liver
项目 1 - 脂肪在肝脏转移植入和扩张中的作用
  • 批准号:
    10331757
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
Determinants of Liver Metastasis
肝转移的决定因素
  • 批准号:
    10895782
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
Determinants of Liver Metastasis
肝转移的决定因素
  • 批准号:
    10738332
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
Determinants of Liver Metastasis
肝转移的决定因素
  • 批准号:
    10331756
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:
The paradoxical roles of beta hydroxy butyrate in the liver pro-metastatic niche
β-羟基丁酸在肝脏促转移生态位中的矛盾作用
  • 批准号:
    10745869
  • 财政年份:
    2020
  • 资助金额:
    $ 11.75万
  • 项目类别:

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