TMIC-75. SPATIALLY-RESOLVED TRANSCRIPTOME ANALYSIS OF BRAIN METASTATIC BREAST CANCER REVEAL KEY MEDIATORS OF BRAIN-TROPIC METASTATIC POTENTIAL

Abstract

Abstract BACKGROUND In women with metastatic breast cancer, 30% (HER2+) to 50% (triple negative) develop brain metastases. Breast-to-brain metastasis carries a poor median survival of only 10 months and is accompanied by severe neurologic decline. Halting the progression of breast cancer brain metastases requires modulation of the tumor microenvironment (TME), yet little is known about how the primary breast TME affects brain tropism, or how, once there, metastatic cancer cells interact with normal brain cells (e.g., neurons, astrocytes, microglia). METHODS We constructed a large (n = 253 cores), diverse, clinically-annotated tissue microarray (TMA) of breast cancer brain metastases with surrounding brain (n = 127), associated primary breast tumors (n = 67, with 30 matched), normal brain (n = 23), and staining control (n = 18) tissue samples, from patients (n = 140) treated at Stanford Hospital between 2008 – 2018. We then leveraged a combination of genome-wide transcriptome analysis and high resolution spatial imaging (using GeoMx Digital Spatial Profiling) to interrogate the distinct, spatially-driven gene signatures of tumor, immune, and normal brain cells within the breast cancer brain metastasis TME. RESULTS We revealed novel gene regulatory programs that are associated with metastatic potential from the primary breast to the brain. We also identified not only diverging features of the breast and brain TMEs, but equivalent features which may contribute to preferential honing and outgrowth of metastatic breast cells in the brain microniche. Additionally, we uncovered significant cellular crosstalk between tumor, immune, and brain cell populations, including putative cell-cell interactions and intercellular signaling pathways. CONCLUSION These results served as a starting point for identifying key tumor-immune-brain interactions responsible for priming immune and brain tolerance of malignant cells, allowing outgrowth and progression of breast cancer brain metastases. Further investigation focused on tumor-brain crosstalk, specifically tumor-microglia interactions, will provide promising targets for therapeutic advancements.