Studying macrophage polarization in search for predictive and prognostic markers of breast cancer

Stanford University, Stanford CA

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Abstract

Project Summary Ductal carcinoma in situ (DCIS) is the most common form of breast cancer, with 50,000 women diagnosed with DCIS annually in the U.S. Although only 20-30% of DCIS lesions will progress to the invasive disease (IDC), 97% of DCIS patients will undergo surgery with or without radiation. Therefore, markers of DCIS progression to IDC are urgently needed to prevent overtreatment. However, the events leading to DCIS progression are unknown, and previous studies have shown that they cannot be explained by genetic and transcriptomic changes in tumor cells. This suggests that elements of the tumor microenvironment (TME) other than cancer cell-intrinsic events might play a role in the transition from in situ to invasive breast cancer. Macrophages are one of the most abundant immune cell type in the TME, that survey the tissue, react to its changes, and orchestrate the immune response, making them ideal biomarker candidates. In the previous funding cycle, we demonstrated that several macrophage subtypes endowed with different functions and relations to cancer exist. We established the first human macrophage subtype-specific markers that, combined with novel formalin-fixed paraffin-embedded (FFPE) tissue-compatible profiling technologies, enable the study of the contribution of individual macrophage subtypes to tumor immunity using archival tissue specimens with known clinical outcome. In addition, we have extensive prior experience with breast carcinoma research and have access to well-studied cohorts of DCIS and IDC with long clinical follow-up. To this end, we found that a higher overall abundance of macrophages in DCIS predicts tumor progression to IDC. In addition, in the preliminary data to this renewal, we reveal a novel and previously overlooked human intraepithelial tissue-resident macrophage population located between the basal and luminal layers of the breast gland and show that it acquires distinct transcriptional signatures upon transition from normal breast epithelium to DCIS, supporting the notion that changes in macrophage compartment might be leveraged as markers of breast cancer development. Aim 1 will study how different macrophage subtypes change in the early events that lead to DCIS tumor formation and progression to IDC, while Aim 2 will seek to identify macrophage-specific markers of tumor progression from DCIS to IBC. Aim 3 will reveal the cellular interactions and molecular signaling shaping different macrophage functions by studying macrophage crosstalk with other tissue cell types, focusing on macrophage interactions with the most abundant TME cells—fibroblasts. The studies in this proposal will improve our understanding of the biology of breast cancer development and identify new prognostic markers and predictors of DCIS progression. Therefore, the proposed research is relevant to the NIH’s mission to develop fundamental knowledge that will help reduce the burdens of human disability and disease.