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

项目总结 乳腺癌的生长和进展需要肿瘤细胞和肿瘤细胞之间复杂的相互作用 周围的环境。浸润性炎症细胞，特别是巨噬细胞数量增加， 与乳腺癌患者预后不良有关。我们的研究重点是找出关键 促进乳腺肿瘤生长和进展的巨噬细胞亚群。基于对 在正常乳腺中，我们已经鉴定出一种间质巨噬细胞群，它与 重塑细胞外基质中的透明质酸，并能够促进肿瘤细胞的侵袭。这些 巨噬细胞定位于肿瘤周围间质中的透明质酸富集区。基于 我们的初步结果是，我们假设这个巨噬细胞亚群代表一个不同的组织 促进乳腺癌进展的居民源性肿瘤相关巨噬细胞群 通过结合和重塑含有透明质酸的细胞外基质。建议进行的研究 特定目标1将使用小鼠模型确定该巨噬细胞亚群的定位和来源 乳腺癌的风险。在具体目标2中提出的研究将勾勒出通过这些关键机制 巨噬细胞参与细胞外基质重塑并驱动肿瘤细胞的侵袭。最后，研究 在具体目标3中提出的将定义这种巨噬细胞亚群在人类乳房中的定位 并使用空间转录组学来确定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广泛的功能多样性在这两个正常 动态平衡和各种疾病，包括癌症。勾勒出有助于 巨噬细胞异质性及其在肿瘤微环境中的功能贡献 对于制定有效针对这一多样化细胞群体的战略至关重要。

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.