Roles of Glial Autophagy in Breast Cancer Brain Metastasis

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PROJECT SUMMARY Recent advance in the prevention and treatment of breast cancer significantly increase the survival of breast cancer patients. It will be highlighted that with the increased survival of breast cancer patients, however, the incidence of latent breast cancer brain metastasis (BCBM) significantly increased. BCBM is one of critical factors that contributes to the lethality of breast cancer patients. Autophagy is important in the initiation and progression of cancers, neurodegenerative diseases, metabolic disorders, and infectious diseases. Nevertheless, the functions of autophagy in tumor microenvironment, especially the roles of glial autophagy in BCBM, are not investigated. Using syngeneic mice, we established intracerebral and intracarotid artery injection models for BCBM with different mouse breast cancer cells. We observed robust astrogliosis, infiltration of microglia, and uncontrolled growth of malignant cells in mouse BCBM models. More importantly, we found increased autophagy in reactive astrocytes but not in neurons at the borders of brain-breast cancers. Using brain specific Fip200 (an autophagy essential gene) conditional knock out mice, we revealed the indispensable functions of autophagy in astrocytes for the initiation and progression of BCBM. Breast cancer cells activated Stat3 to initiate brain metastasis, the process of which depended on intact autophagy in tumor microenvironment astrocytes. Moreover, we confirmed the elevation of autophagy in astrocytes and activation of Stat3 in cancer cells in dissected human samples, suggesting a correlation of our experimental observation with clinical importance. Our results indicated a previously unrecognized mechanism for astrocytes in tumor microenvironment to support the initiation and growth of breast cancer cells in brain. To facilitate mechanistic studies, we generated a coculture model using human breast cancer cell lines with human embryonic stem cells derived cerebral organoids. Our data indicated that the metastatic human MDA-MB-231 breast cancer cells could colonize in cerebral organoids while the non- metastatic MCF-7 cells could not grow. In this proposal, we will determine the molecular mechanisms by which autophagy in astrocytes is utilized by breast cancer for brain metastasis, using a combination of molecular biology, cell tracing method, brain injections, stem cell technology, and mouse genetic approaches. Our proposed studies will have significant impact on understanding the fundamental mechanisms of reactive astrocytes to regulate BCBMs. Our research will raise new translational approach for stratification and treatment of BCBM patients. The results in our research might also shed light on the investigation of tumor microenvironment for other brain metastatic cancers and primary brain tumors.