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.

一个关键的未满足的医疗需求是了解为什么一些患者被诊断出患有激素受体（HR+， 雌激素和孕激素受体阳性； Her2 阴性）乳腺癌复发且远处转移 尽管接受了类似的治疗，但其他人却没有出现转移性疾病。考虑到这一点，这是一个重要问题 大多数被诊断患有乳腺癌并经历转移性复发的患者患有 HR+ 肿瘤。 转移扩散发生得很早，通常在检测到原发肿块之前，并且通过串扰促进 组织和正在发育的肿瘤之间。这产生了正常组织中的差异的可能性 环境的存在会增加转移性疾病的风险。然而，通过这些机制 乳腺组织环境发生变化，其对转移性乳腺癌的影响仍然存在 很大程度上未定义。我们最近建立了肠道共生失调，定义为炎症微生物组 生物多样性低，增强 HR+ 肿瘤的转移。在肿瘤发生前建立生态失调 显着增强肿瘤细胞向血液、远端淋巴结和肺部的扩散，但没有影响 原发性肿瘤生长时。生态失调增强了肥大细胞向正常乳腺组织的积累 的非荷瘤小鼠，而抑制肥大细胞脱颗粒显着减少转移 传播。这些结果表明组织相关肥大细胞在促进 乳腺肿瘤播散。从机制上讲，我们证明在肿瘤发生之前阻断 CCL2 是 足以减少乳腺组织中肥大细胞的积累并减少生态失调引起的 HR+肿瘤细胞的传播。该提案的目标是定义远端肠道共生失调如何 协调非肿瘤小鼠正常乳腺组织的细胞和分子变化 增强对 HR+ 肿瘤传播的易感性。目标 1 将定义共生生态失调如何发生远端变化 正常（非肿瘤）乳腺组织免疫环境有利于早期 HR+ 肿瘤传播。 我们将整合多种方法来研究肠道微生物组、宿主代谢、 和转移性乳腺癌。目标 2 将确定肥大细胞如何促进 HR+ 肿瘤的早期传播。 该目标的目标是确定微生态失调小鼠乳腺组织中的肥大细胞是如何被激活的 并确定肥大细胞如何通过与组织成纤维细胞的相互作用启动 HR+ 肿瘤的转移 巨噬细胞。这些机制研究将有可能揭示新的治疗靶点 预防转移性乳腺癌，这是在肿瘤诊断之前可以识别的目标。考虑到 肠道共生失调的作用、微生物组的改变或共生相关的靶向 代谢物成为预防或减少转移性乳腺发病率的潜在低成本治疗方法 癌症。