Abstract LB-359: Role of metabolic adaptation to the brain microenvironment in facilitating brain metastasis progression

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Abstract Breast cancer is the most commonly diagnosed cancer among American women, with a 1 in 8 lifetime risk of occurrence. The efficacy of treatment of primary tumors is dramatically improving, resulting in prolonged life span; however, given this increase in patient survival, the incidence of metastases is increasing as patients live long enough for metastases to develop. When breast cancer metastasizes to the brain or central nervous system, expected 5-year survival decreases dramatically. Where 5- year survival is 99% for patients with localized disease, it is only 25% for patients with CNS metastases. Further, brain metastases now account for 30% of breast cancer mortality. In breast cancer brain metastasis, interactions between tumor cells and glial cells (the main cell type present in the brain) appear vital to tumor growth and survival under the sub-ideal conditions presented by the unique brain microenvironment. However, the mechanisms through which glial cells support and alter tumor cells, particularly with respect to metabolism are poorly understood. One mechanism by which cells have been found to adapt to metabolic stress is through the transfer of mitochondria from stromal cells. Indeed, mitochondrial transfer has been observed in the central nervous system where glial cells have been found to transfer mitochondria to neurons following ischemic stroke to support neuronal cell viability and recovery. We hypothesize that interactions between tumor cells and glial cells promotes metabolic adaptation to the brain microenvironment. Further, we theorize that this may result from the acquisition of mitochondria derived from glial cells by tumor cells, which may confer a proliferative advantage to the tumor cells. To study this phenomenon, we are utilizing an in vitro system where breast cancer cells are co-cultured with primary murine glial cells. Our initial findings show that that breast cancer cells have decreased proliferation and survival in low glucose/low glutamine growth conditions, which are more representative of the brain environment. Interestingly, the presence of glia provides a survival advantage, and allows the breast cancer cells to survive longer in this condition. We have further found that glia are able to rapidly transfer mitochondria to breast cancer cells. Together, our findings suggest that glial cells play an important role in the progression of breast cancer brain metastases and that mitochondrial transfer may be a novel mechanism by which glial cells protect brain metastatic breast cancer cells. We have planned further experiments to specifically explore the link between the survival phenotype evidenced with the presence of glia to the transfer of mitochondria. Citation Format: Treasa K. O'Tighearnaigh, Erin N. Howe, Patricia M. Schnepp, Siyuan Zhang. Role of metabolic adaptation to the brain microenvironment in facilitating brain metastasis progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-359.