E-103 Inflammation-driven networks in the regulation of breast cancer progression

Accumulating evidence substantiates potent pro-malignancy roles for stromal cells, such as bone marrow-derived mesenchymal stem cells and cancer-associated fibroblasts, in breast cancer. In parallel, the breast tumor microenvironment (TME) is enriched with pro-inflammatory cytokines that play causative roles in promoting disease course. Focusing on the aggressive triple negative subtype of breast cancer (TNBC), we have analyzed by patient dataset studies, in vitro co-culture experiments and in vivo model systems the interactions between TNBC cells, stromal cells and pro-inflammatory cytokines, and their pro-metastatic potential. This integrative approach demonstrated that the stimulation of TNBC:stroma co-cultures by pro-inflammatory cytokines has led to elevated pro-metastatic phenotypes at multiple levels: (1) The expression levels of chemokines that are pro-angiogenic and can lead to high levels of myeloid inflammatory cells at the TME was much increased. (2) The cytokine-stimulated TNBC:stroma co-cultures were enriched with angiogenic factors that promoted endothelial cell sprouting (3) The tumor cells gained high migratory and invasive capabilities. Moreover, studies in animal model systems indicated that TNBC cells that formed contacts with stromal cells in the context of pro-inflammatory stimulation became more aggressive, as indicated by increased incidence of mice having lungmicro-metastases. Molecular studies with siRNA and CRISPR in TNBC cells and/or in stromal cells identified the cellular source for elevated chemokines in cytokine-stimulated TNBC:stroma co-cultures. We have identified the molecules that participate in mediating TNBC:stroma cell-to-cell contacts in the context of pro-inflammatory signals, and the transcription factors regulating these processes. Overall, our findings identified novel players controlling pro-metastatic events TNBC, regulating the triage formed by tumor-stroma-inflammation interactions. These findings pose pro-inflammatory factors as candidate targets whose inhibition may break detrimental networks that promote TNBC progression.