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Roles of Glial Autophagy in Breast Cancer Brain Metastasis

胶质细胞自噬在乳腺癌脑转移中的作用

基本信息

批准号：
10660141
负责人：
Chenran Wang
金额：
$ 40.24万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660141
关键词：
Aging Arteries Astrocytes Autophagocytosis Biological Biology Blood - brain barrier anatomy Blood flow Brain Brain Neoplasms Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Cancer Cell Growth Cancer Patient Cell Maintenance Cells Cerebrum Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Communicable Diseases Cytoplasm Data Dependence Development Developmental Process Disease Disseminated Malignant Neoplasm Essential Genes Exposure to Functional disorder Genes Growth Homeostasis Human Immunosuppression Incidence Infiltration Injections Intracarotid Investigation Knockout Mice Knowledge Lesion MCF7 cell MDA MB 231 Malignant - descriptor Malignant Neoplasms Mediating Mediator Metabolic Metabolic Diseases Metastatic malignant neoplasm to brain Methods Microglia Micrometastasis Modeling Molecular Molecular Biology Monitor Mus Neoplasm Metastasis Neurodegenerative Disorders Neuroglia Neurons Nonmetastatic Oncogenic Organelles Organoids Paracrine Communication Pathologic Pathway interactions Patients Physiological Prevention Primary Brain Neoplasms Primary Neoplasm Process Prognosis Proliferating Quality of life Reporter Research Resistance Role Sampling Signal Pathway Stat3 protein Stratification Structure Synapses System Therapeutic Tropism Tumor Promotion Woman anti-tumor immune response astrogliosis brain parenchyma breast cancer progression breast cancer survival cancer cell cancer stem cell cancer subtypes clinically relevant conditional knockout effective therapy genetic approach human embryonic stem cell human model induced pluripotent stem cell inhibition of autophagy innovation insight malformation malignant breast neoplasm metastasis prevention mouse genetics mouse model neoplastic cell neuropathology neurotransmission novel paracrine pharmacologic polyoma middle tumor antigen pressure prevent response self organization stem cell technology translational approach triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression

项目摘要

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.

项目总结