Interplay between host microbiome and immunomodulatory responses in the pathogenesis of Kras mutant lung cancer

Kras 突变肺癌发病机制中宿主微生物组与免疫调节反应之间的相互作用

基本信息

批准号：
10356940
负责人：
Humam Kadara
金额：
$ 54.07万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2021-02-19 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356940
关键词：
16S ribosomal RNA sequencing 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Address Animals Antibiotics Antibodies Bioinformatics Cancer Patient Carcinogen exposure Cells Chemoprevention Chemopreventive Agent Clinical Cues Data Development Disease Early Diagnosis Early treatment Event Evolution Exhibits Experimental Models Exposure to Fostering G-Protein-Coupled Receptors Genetic Genetically Engineered Mouse Global Change Health Host Defense Human Immune Immune response Immunotherapeutic agent Immunotherapy Inferior Inflammation Inflammatory Interleukin-6 Intervention Ketones Knock-out LCN2 gene Light Link Lung Lung Adenocarcinoma Lung immune response Malignant Neoplasms Malignant neoplasm of lung Mediating Metagenomics Modality Molecular Target Mus Mutation Neoadjuvant Therapy Nicotine Nitrosamines Oncogenes Outcome Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phenotype Prevention strategy Process Prognosis Proteins Pulmonary Inflammation Reporting Role STAT3 gene Sampling Signal Transduction Smoker Smoking Somatic Mutation Structure of parenchyma of lung Study models T-Lymphocyte Taxonomy Testing Therapeutic Effect Time Tobacco Tobacco-Associated Carcinogen Tumor Immunity United States Up-Regulation Variant Volatile Fatty Acids Wild Type Mouse antimicrobial cancer diagnosis cancer therapy cigarette smoke combustible cigarette exposure to cigarette smoke gut microbiome host microbiome immune checkpoint immunoregulation insight lung microbiome microbial microbiome microbiome composition mouse model mutant novel nursing mothers prevent probiotic supplementation programmed cell death protein 1 programs response statistics tobacco exposure treatment response tumor tumor immunology tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Lung adenocarcinoma (LUAD) is the most common cancer diagnosed in lifetime smokers of whom there are more than 90 million in the United States. Smokers with LUAD frequently (more than 25%) harbor somatic activating mutations in the Kras oncogene. Kras-mutant LUAD (KM-LUAD) displays very poor clinical outcome and inferior response to therapy. Despite the urgent need of new strategies for early treatment of this fatal disease, we still do not understand targetable changes that promote onset of KM-LUAD. Using a human- relevant genetically engineered mouse model comprised of tobacco exposure and high somatic mutation burdens including driver Kras variants, features that constitute a perfect storm for LUAD pathogenesis in humans, we identified significant progressive changes in gut microbiome composition that were coexistent with reduced levels of gut and circulating bacterial metabolites and closely associated with evolution of KM-LUAD. Similar microbial phenotypes were observed in mice exposed to combustible cigarette smoke (CCS). We further found in lungs of the mice up-regulation of pro-tumor inflammatory cues including activation of the IL-6 /STAT3 pathway which we have previously shown to promote KM-LUAD development by immune reprogramming. Also, we noted that lipocalin 2 (LCN2), a host defense antimicrobial protein that is released from cells during microbiome imbalance, was markedly progressively up-regulated in normal airway cells prior to onset of Kras-mutant preneoplasias and LUADs. Genetic deletion of Lcn2 in these mice markedly increased KM-LUAD development concomitant with global changes in the gut microbiome and heightened pro-tumor lung inflammation. Despite these insights, the interplay between the host microbiome and key immune responses in the pathogenesis of KM-LUAD are poorly understood. We hypothesize that the host microbiome (derived from the gut and possibly the lung) promotes tobacco-associated KM-LUAD development through activation of the IL-6/STAT3 pathway and changes in systemic and lung immune contexture. We will address our hypothesis using the following three aims. In Aim 1, using sequencing, metagenomics, as well as bacterial metabolite and immune profiling approaches, we will discern evolving microbiome changes that are functionally linked to tobacco carcinogen- and CCS-associated KM-LUAD development as well as probe downstream systemic and local (in lung) immunomodulatory effects including those on the pro-tumor IL- 6/STAT3 pathway. In Aim 2, we will determine the role of host antimicrobial and immunomodulatory cues mediated by LCN2 induction in KM-LUAD pathogenesis. In Aim 3, we will investigate chemopreventive and early therapeutic effects of microbiome intervention, alone or in combination with immunotherapy, against KM- LUAD. At the conclusion of our studies, we will have shed light on uncharted host processes in the evolution of KM-LUAD, paved the way for identification of new targets to guide chemoprevention and early detection of this fatal disease in smokers and contributed novel models for studying LUAD pathogenesis.

项目概要肺腺癌 (LUAD) 是终生吸烟者中最常见的癌症美国超过9000万。患有 LUAD 的吸烟者经常（超过 25%）患有躯体疾病激活 Kras 癌基因的突变。 Kras 突变体 LUAD (KM-LUAD) 的临床结果非常差以及对治疗的反应较差。尽管迫切需要新的策略来早期治疗这种致命的疾病疾病，我们仍然不了解促进 KM-LUAD 发作的针对性改变。使用人类- 由烟草暴露和高体细胞突变组成的相关基因工程小鼠模型包括驱动程序 Kras 变体在内的负担，这些特征构成了 LUAD 发病机制的完美风暴在人类中，我们发现肠道微生物组组成发生了显着的渐进性变化，这些变化与肠道和循环细菌代谢物水平降低，与 KM-LUAD 的进化密切相关。在暴露于可燃香烟烟雾（CCS）的小鼠中观察到类似的微生物表型。我们在小鼠肺部进一步发现促肿瘤炎症信号的上调，包括 IL-6 的激活 /STAT3 通路，我们之前已经证明可以通过免疫促进 KM-LUAD 的发育重新编程。此外，我们还注意到脂质运载蛋白 2 (LCN2)，一种释放的宿主防御抗菌蛋白在微生物组失衡期间来自细胞，在正常气道细胞中显着逐渐上调 Kras 突变癌前病变和 LUAD 的发生。这些小鼠中 Lcn2 的基因缺失显着增加 KM-LUAD 的发展伴随着肠道微生物组的整体变化和促肿瘤肺的增强炎。尽管有这些见解，宿主微生物组与关键免疫反应之间的相互作用 KM-LUAD 的发病机制尚不清楚。我们假设宿主微生物组（衍生来自肠道，也可能来自肺部）通过以下方式促进与烟草相关的 KM-LUAD 发育： IL-6/STAT3 通路的激活以及全身和肺部免疫环境的变化。我们将使用以下三个目标来解决我们的假设。在目标 1 中，使用测序、宏基因组学以及细菌代谢和免疫分析方法，我们将辨别不断变化的微生物组变化与烟草致癌物和 CCS 相关的 KM-LUAD 开发以及探针功能相关下游全身和局部（肺）免疫调节作用，包括对促肿瘤 IL- 的作用 6/STAT3 途径。在目标 2 中，我们将确定宿主抗菌和免疫调节线索的作用 KM-LUAD 发病机制中由 LCN2 诱导介导。在目标 3 中，我们将研究化学预防和单独或与免疫疗法联合微生物组干预对 KM-的早期治疗效果卢阿德。在我们的研究结束时，我们将揭示进化过程中未知的宿主过程。 KM-LUAD 为识别新靶点以指导化学预防和早期检测铺平了道路吸烟者的致命疾病，并为研究 LUAD 发病机制提供了新的模型。