Defining the contributions of Lyve-1 expressing macrophages to breast cancer growth and progression

项目摘要 乳腺癌的生长和进展需要肿瘤细胞与它们之间复杂的相互作用。 周边环境浸润性炎性细胞，特别是巨噬细胞数量增加， 与乳腺癌患者预后不良相关。我们的研究集中在确定关键的 巨噬细胞亚群有助于乳腺肿瘤的生长和进展。根据研究， 在正常乳腺中，我们已经确定了一个基质巨噬细胞群， 重塑细胞外基质中的透明质酸，并且能够促进肿瘤细胞侵袭。这些 巨噬细胞特异性地定位于肿瘤周围基质中富含透明质酸的区域。基于 根据我们的初步结果，我们假设这种巨噬细胞亚群代表了一种独特的组织， 导致乳腺癌进展的居民源性肿瘤相关巨噬细胞群 通过结合和重塑含透明质酸的细胞外基质。拟议的研究 具体目标1将使用小鼠模型定义该巨噬细胞亚群的定位和来源 乳腺癌具体目标2中提出的研究将描述这些目标的关键机制， 巨噬细胞有助于细胞外基质重塑并驱动肿瘤细胞侵袭。最后，研究 在特定目标3中提出的方法将定义该巨噬细胞亚群在人乳腺中的定位 癌症，并使用空间转录组学来识别这些巨噬细胞周围的局部环境。 最近的研究强调了巨噬细胞在两种正常组织中广泛的功能多样性， 体内平衡和各种疾病，包括癌症。描述有助于实现这一目标的具体机制 巨噬细胞的异质性，并确定其在肿瘤微环境中的功能贡献 对于开发有效靶向这种多样化细胞群体的策略至关重要。

PROJECT SUMMARY Breast cancer growth and progression require complex interactions between tumor cells and their surrounding environment. Increased numbers of infiltrating inflammatory cells, in particular macrophages, correlate with poor patient prognosis in breast cancer. Our studies have focused on identifying key macrophage subpopulations that contribute to mammary tumor growth and progression. Based on studies in the normal mammary gland, we have identified a stromal macrophage population that is associated with remodeling hyaluronan in the extracellular matrix and is capable of promoting tumor cell invasion. These macrophages are localized specifically to hyaluronan-enriched regions in the peri-tumoral stroma. Based on our preliminary results, we hypothesize that this macrophage subpopulation represents a distinct tissue resident-derived tumor associated macrophage population that contributes to breast cancer progression through binding to and remodeling the hyaluronan-containing extracellular matrix. Studies proposed in Specific Aim 1 will define the localization and source of this macrophage subpopulation using mouse models of breast cancer. Studies proposed in Specific Aim 2 will delineate the key mechanisms through which these macrophages contribute to extracellular matrix remodeling and drive tumor cell invasion. Finally, studies proposed in Specific Aim 3 will define the localization of this macrophage subpopulation in human breast cancers and use spatial transcriptomics to identify the local environment surrounding these macrophages. Recent studies have highlighted the extensive functional diversity of macrophages in both normal homeostasis and in various diseases, including cancer. Delineating the specific mechanisms that contribute to macrophage heterogeneity and defining their functional contributions within the tumor microenvironment are critical for developing strategies to effectively target this diverse population of cells.