Role of microbial-modulated bile acid receptor signaling in breast cancer

微生物调节胆汁酸受体信号传导在乳腺癌中的作用

基本信息

项目摘要

SUMMARY Anti-tumor immunity varies due to interactions between innate and adaptive immune cells, microbial community diversity, host and microbially derived metabolites, and other local factors that shape tumoricidal responses. While most of the recent microbiome research focuses on the gut microbiome and cancer outcomes, extra-intestinal microbial communities are detected in the tumor microenvironment (TME). We recently reported that specific microbes identified in patient breast tumors compared to pathologically normal breast samples associated with tumor stage, tumor subtype, and for the first time, race. Triple Negative Breast Cancer (TNBC), an aggressive subtype that has generally eluded personalized medicine approaches, contained unique microbes that may mediate immunosuppression and impact standard chemotherapy or immune checkpoint inhibitor (ICI) efficacies. Yet to date, mechanisms underpinning these observations are unresolved as to how the gut and/or extra-intestinal microbiome influence BC onset, progression, and response to therapies, which is a major knowledge gap in this field. One cogent mechanism that may link microbes to anti-tumor immunity are microbially modified metabolites, namely bile acids. Certain microbes rich in 7-alpha-hydroxylase convert primary to secondary bile acids which regulate bile acid composition. Bile acids have been shown to limit progression and metastasis in other cancers through reversing immunosuppression, but minimal work has explored the role of bile acids in BC. Bile acids signal through several bile acid receptors including farnesoid X receptor (FXR). We posit that specific gut or local resident microbes that impact bile acid pools and composition will interact with cells expressing FXR to regulate the TME immune milieu. We report for the first time that patients with high FXR expression have greater relapse-free survival uniquely in TNBC subtype, but not in less aggressive luminal BC subtype, suggesting potential for targeted approaches. The overall objective of this proposal is to test mechanisms linking MicrobesBile AcidsTNBC which poses an opportunity to generate novel therapeutics and precision medicine informed by microbial compositions. Our innovative approach interrogates targetable microbial pathways that we demonstrate change the microbiome, bile acids, and tumor progression. Our central hypothesis is microbial composition and microbially-modified metabolic products, such as bile acids, increase immunotherapeutic efficacy through reprogramming the TME leading to enhanced anti-tumor immunity. We will test our hypothesis by performing the following aims: 1) Determine if commensal microbes play a physiological role in TNBC anti-tumor immunity; 2) Determine if the microbiome alters immunosurveillance of early tumor onset and progression; 3) Determine if pharmacologic bile acid receptor agonism improves TNBC immunotherapy. Findings generated will have high impact because the lack of targeted therapies for TNBC presents a great unmet clinical need and could be transformative to improve patient outcomes.
总结

项目成果

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Liza Makowski-Hayes其他文献

Liza Makowski-Hayes的其他文献

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{{ truncateString('Liza Makowski-Hayes', 18)}}的其他基金

Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model
使用新型临床前模型确定三阴性乳腺癌的易感位点
  • 批准号:
    10573287
  • 财政年份:
    2022
  • 资助金额:
    $ 41.73万
  • 项目类别:
Determining the contribution of microbial-derived metabolites to protective immunity in obesity-driven cancer risk.
确定微生物衍生的代谢物对肥胖驱动的癌症风险中的保护性免疫的贡献。
  • 批准号:
    10505372
  • 财政年份:
    2022
  • 资助金额:
    $ 41.73万
  • 项目类别:
Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model
使用新型临床前模型确定三阴性乳腺癌的易感位点
  • 批准号:
    10444546
  • 财政年份:
    2022
  • 资助金额:
    $ 41.73万
  • 项目类别:
Role of microbial-modulated bile acid receptor signaling in breast cancer
微生物调节胆汁酸受体信号传导在乳腺癌中的作用
  • 批准号:
    10404525
  • 财政年份:
    2020
  • 资助金额:
    $ 41.73万
  • 项目类别:
Role of microbial-modulated bile acid receptor signaling in breast cancer
微生物调节胆汁酸受体信号传导在乳腺癌中的作用
  • 批准号:
    10219210
  • 财政年份:
    2020
  • 资助金额:
    $ 41.73万
  • 项目类别:
Role of microbial-modulated bile acid receptor signaling in breast cancer
微生物调节胆汁酸受体信号传导在乳腺癌中的作用
  • 批准号:
    10614037
  • 财政年份:
    2020
  • 资助金额:
    $ 41.73万
  • 项目类别:
(PQA2) Reversing Carcinogenic Effect of Obesity on Basal-like Breast Cancer
(PQA2) 逆转肥胖对基底样乳腺癌的致癌作用
  • 批准号:
    8590946
  • 财政年份:
    2013
  • 资助金额:
    $ 41.73万
  • 项目类别:
Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity
炎症、胰岛素抵抗中的巨噬细胞线粒体应激
  • 批准号:
    8208231
  • 财政年份:
    2007
  • 资助金额:
    $ 41.73万
  • 项目类别:
Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity
炎症、胰岛素抵抗中的巨噬细胞线粒体应激
  • 批准号:
    8121191
  • 财政年份:
    2007
  • 资助金额:
    $ 41.73万
  • 项目类别:
Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity
炎症、胰岛素抵抗中的巨噬细胞线粒体应激
  • 批准号:
    7479191
  • 财政年份:
    2007
  • 资助金额:
    $ 41.73万
  • 项目类别:

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