Prevention of Brain Metastasis Relapse through Modulation of Age-related Gut Microbiota-Immune Cross talk

通过调节与年龄相关的肠道微生物群-免疫串扰来预防脑转移复发

基本信息

批准号：
10287850
负责人：
Siyuan Zhang
金额：
$ 21.95万
依托单位：
UNIVERSITY OF NOTRE DAME
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：
2021-08-03 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287850
关键词：
Affect Age Aging Animal Model Award Biological Response Modifier Therapy Brain Brain Neoplasms Breast Cancer Patient Breast Cancer survivor Cancer Etiology Cancer Patient Cancer Survivor Cells Cellular Structures Clinical Communities Diagnosis Disease Encephalitis Equilibrium Female Future Genomics Goals Homeostasis Immune Immune response Immune system Immunity Immunologic Surveillance Immunotherapy Inflammaging Link Malignant neoplasm of brain Metagenomics Metastatic malignant neoplasm to brain Modeling Molecular Neoplasm Metastasis Neurosciences Pathogenicity Patients Peripheral Pharmacotherapy Phenotype Play Population Prevention Primary Neoplasm Probiotics Process Prognosis Recurrence Relapse Role System Testing Therapeutic Treatment Efficacy age related aged base cancer immunotherapy cancer prevention cancer therapy clinically actionable combat cost effective design dysbiosis gut dysbiosis gut microbiota gut-brain axis host microbiota improved individualized medicine insight malignant breast neoplasm metastasis prevention microbiota microorganism mortality neoplastic cell nervous system disorder neuroinflammation novel novel therapeutics pre-clinical prevent probiotic therapy reconstitution single cell analysis success

项目摘要

Project Summary Metastasis is the major cause of cancer mortality, with brain metastasis being the most aggressive and incurable form of metastatic recurrence. The prognosis for breast cancer patients with brain metastasis is devastatingly poor with a median survival of less than six months. Brain metastasis relapse depends on the intricate interplay between disseminated tumor cells and components of the brain metastatic microenvironment - the niche. To combat breast cancer mortality, it is imperative to develop rationally-designed strategies to prevent brain metastasis relapse. The immune system plays a significant role in regulating both primary and metastatic tumors. The gut microbiota - an ecological community of commensal, symbiotic, and pathogenic microorganisms consistently primes and reshapes the immune surveillance system during aging. Mounting evidence in the neuroscience field demonstrated a clear connection between gut microbiota dysbiosis and brain inflammation as well as various neurological diseases. As brain metastasis relapse often occurs in aged breast cancer survivors, in this proposed study, we will focus on delineating mechanisms by which the microbiota-host immune interaction influences metastatic progression in the aged female population. We postulate that age-related gut dysbiosis may reshape the brain immune metastatic niche to influence brain metastatic relapse. Our overarching goal is to dissect the mechanistic connection between gut dysbiosis and brain metastasis relapse and identify clinically actionable probiotics modulation strategies tailored to aged breast cancer survivors to prevent brain metastatic relapse. Based on well-established aging models, cutting-edge single-cell genomics, and metagenomics approaches, we will examine molecular changes in brain metastatic tumors with gut microbiota alterations in the aged host. Then design and test targeted microbiota-modulation strategies to prevent brain metastatic relapse in aged hosts. This project is the first attempt to explore the mechanistic link between the gut microbiota and breast cancer brain metastatic niche in the aging context. From the cancer prevention perspective, mechanistic insights via examining age-associated dysbiosis in regulating brain metastasis relapse will guide personalized microbiota-modulation strategy that is tailored to each breast cancer survivor to prevent deadly brain metastatic relapse.

项目摘要转移是癌症死亡率的主要原因，脑转移是最具侵略性的，无法治愈的转移性复发形式。脑转移患乳腺癌患者的预后是毁灭性的贫穷，中位生存期少于六个月。脑转移复发取决于在传播肿瘤细胞和脑转移微环境的成分之间复杂的相互作用 - 利基。为了打击乳腺癌的死亡率，必须制定理性设计的策略防止脑转移复发。免疫系统在调节原发性和转移性肿瘤方面起着重要作用。肠道微生物群 - 一个共生，共生和致病微生物的生态群落始终如一衰老期间的素料和重塑免疫监视系统。神经科学中的越来越多的证据田野表明肠道菌群营养不良与脑部炎症以及各种神经系统疾病。由于脑转移复发经常发生在老年乳腺癌幸存者中，因此拟议的研究，我们将重点介绍描述微生物群免疫相互作用的划定机制影响老年女性人群的转移性进展。我们假设与年龄相关的肠道营养不良可能会重塑脑免疫转移性生态位以影响脑转移性复发。我们的总体目标是剖析肠道营养不良与脑转移复发之间的机械联系并识别针对老年乳腺癌幸存者量身定制的临床可行的益生菌调制策略，以防止大脑转移性复发。基于建立良好的衰老模型，尖端的单细胞基因组学和宏基因组学方法，我们将检查脑转移性肿瘤的分子变化老年主机的变化。然后设计和测试目标微生物群调节策略以防止大脑老年宿主的转移性复发。该项目是探索肠道菌群与乳房之间机械联系的首次尝试在衰老的情况下，癌症脑转移性生态位。从预防癌症的角度来看通过检查与年龄相关的营养不良来调节脑转移复发的见解将指导个性化微生物群调节策略是针对每个乳腺癌幸存者量身定制的，以防止致命的大脑转移性复发。