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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

批准号：
10053592
负责人：
Liza Makowski-Hayes
金额：
$ 41.73万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10053592
关键词：
7alpha hydroxylase Ablation Address Adjuvant Affect Aggressive behavior Agonist Antibiotics Bile Acids Blood Circulation Body Weight decreased Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cell Communication Cells Clinical Data Dietary Intervention Enterohepatic Circulation Estrogen Receptors Generations Genetic Goals Growth Human Hydroxylation Immune Immune checkpoint inhibitor Immunologic Surveillance Immunosuppression Immunotherapeutic agent Immunotherapy Implant In Vitro Incidence Intestinal Neoplasms Intestines Knowledge Link Liver Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Mediator of activation protein Metabolic Microbe Modeling Modification Mus Neoplasm Metastasis Obesity Outcome Pathologic Pathway interactions Patient-Focused Outcomes Patients Pharmacology Physiological Play Primary carcinoma of the liver cells Race Receptor Signaling Relapse Reporting Role Sampling Secondary to Shapes Signal Transduction Stromal Cells Testing Therapeutic Time Tissues Treatment Efficacy Tumor Immunity Tumor Markers Tumor Subtype Tumor stage Weight Work bacterial metabolism bariatric surgery breast cancer progression cancer cell cancer immunotherapy cancer subtypes carcinogenicity chemotherapy commensal microbes experimental study fecal transplantation gain of function gut microbiome gut microbiota host microbiota improved innovation malignant breast neoplasm microbial microbial community microbiome microbiome alteration microbiome research microbiota migration mimetics nonhuman primate novel novel therapeutics personalized medicine precision medicine receptor receptor expression response small molecule targeted treatment therapeutic evaluation triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression tumor-immune system interactions

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