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

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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.