Gut microbiome-mediated differences within the pre-malignant mammary tissue environment enhance early breast tumor metastasis

恶变前乳腺组织环境中肠道微生物介导的差异增强了早期乳腺肿瘤转移

• 批准号: 10594667
• 负责人: Melanie R Rutkowski
• 金额: $ 44.92万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594667
• 关键词: Adoptive Transfer; Affect; Benign; Bile Acids; Biodiversity; Blood; Breast; Breast Cancer Patient; CCL2 gene; Cell Communication; Cell Degranulation; Cells; Clinical; Data; Detection; Diagnosis; Dinoprostone; Disease; Disease Outcome; Distal; Distant; Drug Combinations; Environment; Estrogen Receptors; Fibroblasts; Gene Expression; Genomics; Goals; Growth; Histologic; Homeostasis; Hormone Receptor; Immune; Immunofluorescence Immunologic; Incidence; Individual; Inflammation; Inflammatory; Insulin Resistance; Intervention; Link; Lung; Macrophage; Mammary Gland Parenchyma; Mammary Neoplasms; Mediating; Medical; Metabolic; Metabolism; Metastatic breast cancer; Modeling; Modification; Molecular; Mus; Neoplasm Metastasis; Newly Diagnosed; Normal tissue morphology; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Predisposition; Prevention; Primary Neoplasm; Recurrence; Relapse; Reporter; Risk; Role; Sampling; Signal Pathway; Testing; Therapeutic; Tissues; Tumor-associated macrophages; Up-Regulation; Woman; Work; acylcarnitine; clinically relevant; cost; dysbiosis; epidemiology study; experience; gut microbiome; gut microbiota; high risk; hormone receptor-positive; lymph nodes; malignant breast neoplasm; mammary; mast cell; microbial; microbiome; mortality; mouse model; neoplastic cell; new therapeutic target; novel; pharmacologic; premalignant; prevent; progesterone receptor positive; recruit; response; restoration; treatment response; tumor; tumor diagnosis; tumor growth; tumor initiation; tumor microenvironment

A critical unmet medical need is to understand why some patients diagnosed with hormone receptor (HR+, estrogen- and progesterone-receptor positive; Her2 negative) breast cancer experience recurrences with distant metastatic disease whereas others do not, despite similar treatment. This is a significant issue considering that the majority of patients diagnosed with breast cancer and that experience metastatic relapse have HR+ tumors. Metastatic spread occurs early, often prior to the detection of the primary mass, and is facilitated by crosstalk between the tissue and developing tumor. This gives rise to the possibility that differences in the normal tissue environment exist which enhance the risk for metastatic disease. However, the mechanisms through which changes arise in the mammary tissue environment and their contributions to metastatic breast cancer remain largely undefined. We recently established gut commensal dysbiosis, defined as an inflammatory microbiome with low biodiversity, enhances metastasis of HR+ tumors. Establishing dysbiosis prior to tumor initiation significantly enhanced dissemination of tumor cells into the blood, distal lymph nodes, and lungs, with no impact upon primary tumor growth. Dysbiosis enhanced the accumulation of mast cells into the normal mammary tissue of non-tumor-bearing mice, whereas inhibition of mast cell degranulation significantly reduced metastatic dissemination. These results indicated an important role for tissue-associated mast cells in the promotion of breast tumor dissemination. Mechanistically, we demonstrate that blockade of CCL2 prior to tumor initiation is sufficient to reduce mast cell accumulation in the mammary tissue and to diminish dysbiosis-induced dissemination of HR+ tumor cells. The goal of this proposal is to define how gut commensal dysbiosis distally orchestrates cellular and molecular changes in normal mammary tissues of non-tumor-bearing mice that enhance susceptibility to HR+ tumor dissemination. Aim 1 will define how commensal dysbiosis distally changes the normal (non-tumor-bearing) mammary tissue immune environment to favor early HR+ tumor dissemination. We will integrate a variety of approaches to investigate the link between the gut microbiome, host metabolism, and metastatic breast cancer. Aim 2 will establish how mast cells promote early dissemination of HR+ tumors. The goal of this aim will be to define how mast cells are activated in mammary tissues of mice with dysbiosis and establish how mast cells initiate metastasis of HR+ tumors through interactions with tissue fibroblasts and macrophages. These mechanistic studies will have the potential to unveil novel therapeutic targets for the prevention of metastatic breast cancer, targets that could be identifiable prior to a tumor diagnosis. Considering the role of the gut commensal dysbiosis, modification of microbiome or targeting of commensal-associated metabolites emerges as a potential low cost therapeutic to prevent or reduce the incidence of metastatic breast cancer.

关键的未满足医学需求是了解为什么一些被诊断为激素受体的患者（HR+， 雌激素和孕激素受体阳性； HER2阴性）乳腺癌经历远处复发 转移性疾病，而其他疾病则没有类似的治疗方法。考虑到这是一个重要的问题 大多数被诊断出患有乳腺癌和这种转移性复发的患者患有HR+肿瘤。 转移性扩散早在检测原质量之前，通常在检测前发生，并通过串扰来促进 在组织和发展肿瘤之间。这引起了正常组织差异的可能性 存在环境，可以增强转移性疾病的风险。但是，通过 乳腺组织环境中会发生变化，它们对转移性乳腺癌的贡献仍然存在 在很大程度上不确定。我们最近建立了肠道共生失调，被定义为炎症微生物组 生物多样性低，可以增强HR+肿瘤的转移。在肿瘤开始之前建立营养不良 显着增强了肿瘤细胞对血液，远端淋巴结和肺的传播，没有影响 原发性肿瘤生长。营养不良增强了肥大细胞的积累到正常的乳腺组织 非肿瘤的小鼠的抑制作用，肥大细胞脱粒显着降低了转移性 传播。这些结果表明与组织相关的肥大细胞在促进中起重要作用 乳腺肿瘤传播。从机械上讲，我们证明了在肿瘤开始之前对CCL2的封锁是 足以减少乳腺组织中的肥大细胞积累并减少营养不良诱导的 HR+肿瘤细胞的传播。该提议的目的是定义肠道共生失调如何远端 在非肿瘤小鼠的正常乳腺组织中策划细胞和分子变化， 增强对HR+肿瘤传播的敏感性。 AIM 1将定义共生失调的远端变化 正常的（非肿瘤）乳腺组织免疫环境有利于早期HR+肿瘤传播。 我们将整合各种方法来研究肠道微生物组，宿主代谢之间的联系， 和转移性乳腺癌。 AIM 2将确定肥大细胞如何促进HR+肿瘤的早期传播。 该目标的目的是定义如何在患有营养不良的小鼠的乳腺组织中激活肥大细胞 并建立肥大细胞如何通过与组织成纤维细胞相互作用和 巨噬细胞。这些机械研究将有可能公布新的治疗靶标的 预防转移性乳腺癌，可以在肿瘤诊断之前可以识别的靶标。考虑 肠道共生失调，微生物组的修饰或共同相关的靶向作用 代谢物作为预防或减少转移性乳房发生的潜在低成本治疗方法 癌症。