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

一个关键的未满足的医疗需求是了解为什么一些患者诊断为激素受体（HR+， 雌激素和孕酮受体阳性; Her 2阴性）乳腺癌复发， 转移性疾病，而其他人没有，尽管类似的治疗。这是一个重要的问题， 大多数诊断为乳腺癌并经历转移复发的患者具有HR+肿瘤。 转移性扩散发生较早，通常在原发性肿块被发现之前，并且由串扰促进 组织和肿瘤之间的联系这就产生了正常组织中的差异 环境的存在增加了转移性疾病的风险。然而，通过这些机制， 乳腺组织环境发生变化， 大部分未定义。我们最近建立了肠道微生态失调，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 显著增强肿瘤细胞向血液、远端淋巴结和肺部的扩散， 原发性肿瘤生长。乳腺组织中肥大细胞的聚集增加 而抑制肥大细胞脱颗粒显著降低了转移性 传播。这些结果表明，组织相关肥大细胞在促进细胞增殖中起重要作用。 乳腺肿瘤播散。从机制上讲，我们证明了在肿瘤发生之前阻断CCL 2， 足以减少肥大细胞在乳腺组织中的积累，并减少生态失调诱导的 HR+肿瘤细胞播散。这项提案的目的是确定肠道微生态失调如何从远端 协调非荷瘤小鼠正常乳腺组织的细胞和分子变化， 增强HR+肿瘤播散的易感性。目标1将定义远端的肠道生态失调是如何变化的 正常（非荷瘤）乳腺组织免疫环境有利于早期HR+肿瘤扩散。 我们将整合各种方法来研究肠道微生物组，宿主代谢， 和转移性乳腺癌。目的2将确定肥大细胞如何促进HR+肿瘤的早期播散。 本研究的目的是明确肥大细胞在微生态失调小鼠乳腺组织中的激活机制 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， 转移性乳腺癌的预防，可以在肿瘤诊断之前识别的目标。考虑 肠道菌群失调的作用，微生物组的修饰或靶向与肠道菌群相关的 代谢物作为潜在的低成本治疗剂出现，以预防或减少转移性乳腺癌的发生率。 癌

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.