Dissecting Inflammatory Regulatory Network Mediating Metastasis in Triple-Negative Breast Cancers

Metastasis represents the most frequent cause of breast cancer patient death. Tumor microenvironment (i.e. the interaction between cancer cells and immune cells) plays important roles during breast cancer metastasis. However, it remains largely unknown how the compositions and gene signatures of tumor microenvironment differ between metastatic breast cancers versus in situ ones. Here I propose to use high-throughput genomic technologies and computational modeling to systematically examine genome-wide gene expression profiles in synergistic mouse cancer models representing different oncogenic stages. I hypothesize that metastatic breast cancers can introduce a more inflammatory microenvironment, promoting cancer invasiveness and aggressiveness. Using single-cell RNA sequencing experiments, we will decode the tumor composition of stromal/immune cell types and associated gene signatures. Furthermore, we will reconstruct gene transcriptional network mediating cancer cells and associated CD8+ T-cells, integrating chromatin accessibility and RNA expression profiles. Through the comparison of epigenetic landscape and gene expression profiles between metastatic and in situ breast tumors, we will provide novel mechanistic insights of cancer metastasis and reveal novel cancer therapeutic strategies for precision medicine and immunotherapy.