Cancer Proliferation at the Brain Metastatic Site: A Proteomic Exploration of Inter-Cellular Cross-talk Sustained by Cell-membrane/Secretome Interactions
| dc.contributor.author | Zhang, Yunqian | en |
| dc.contributor.committeechair | Lazar, Maria Iuliana | en |
| dc.contributor.committeemember | Hsu, Bryan | en |
| dc.contributor.committeemember | Lamouille, Samy | en |
| dc.contributor.committeemember | Li, Liwu | en |
| dc.contributor.department | Biological Sciences | en |
| dc.date.accessioned | 2025-01-22T09:01:18Z | en |
| dc.date.available | 2025-01-22T09:01:18Z | en |
| dc.date.issued | 2025-01-21 | en |
| dc.description.abstract | Brain metastasis of breast cancer is one of the leading causes of mortality in patients suffering from cancer. The unique structure and components of the brain microenvironment, including the brain-blood barrier and the immune-suppressive environment, present significant clinical challenges to treating brain metastatic breast cancers. This study has hypothesized that the thriving of metastatic breast cancer cells within the brain is driven by the complex interactions between cancer cells and the brain tumor microenvironment, which is reshaped into a tumor-permissive environment. Therefore, by utilizing mass spectrometry-based proteomic analysis, this study focused on analyzing the secretome and cell surfaceome of metastatic breast cancer and brain-residential cells to reveal the interactions between these cells and contribution to various cancer-developing biological processes, including cell growth and proliferation, cell death and apoptosis, immune modulation, angiogenesis, extracellular matrix organization, and epithelial-mesenchymal transition. The project was conducted in three tiers: (1) profiling the secreted and cell membrane proteins, (2) mapping ligand-receptor interactions using an in-house ligand-receptor database, and (3) determining the functional roles of the interacting ligands and receptors. The analysis revealed a complex network of intercellular communications demonstrating how the cancer cells could potentially influence the brain residential cells and, conversely, how the brain cells could influence the cancer cells and contribute to reshaping the tumor microenvironments to support cancer progression. 3D co-culture spheroid models further underlined the influence of cell-cell interactions on tumor growth. Altogether, this work provides an integrated approach to understanding the molecular cross-talk within the brain tumor microenvironment and in-depth insights into potential therapeutic targets to disrupt tumor-promoting changes in the brain metastatic niche. | en |
| dc.description.abstractgeneral | Breast cancer is one of the most prevalent cancers among women in the US, and metastatic cancer remains the leading cause of cancer deaths. The spread of breast cancer to the brain is particularly challenging because of the special conditions within the brain, including the protective blood-brain barrier, specialized stromal cells, and immunosuppressive microenvironment. It is important to understand how the cells of primary breast cancer survive and grow in the brain with the aim of improving treatment. This study has hypothesized that the thriving of metastatic breast cancer cells within the brain is driven by the complex interactions between cancer cells and the brain tumor microenvironment, which is reshaped into a tumor-permissive environment. This study also explored the processes by which breast cancer cells interface with and restructure the brain microenvironment to support tumor growth and survival. We aimed to (1) profile secreted and cell surface proteins, (2) map ligand-receptor interactions based on a custom pairing database, and (3) investigate the functional roles of these interactions in the brain metastatic niche. Employing advanced mass spectrometry, we identified a complex network of pathways that could drive communication between cancer and brain cells, and mediate biological processes that include tumor growth, suppression of immune response, and blood vessel formation. Moreover, by co-culturing cancer and brain cells together in 3D spheroid models, we observed how the presence of brain cells would affect the cancer cell behavior. This study elucidates very important features that could enable breast cancer cells to thrive in the brain and also highlights possible ways to disrupt such deleterious interactions. Ultimately, this study contributes to opening the door to finding new treatment strategies that can improve the outlook for patients with brain metastatic cancer. | en |
| dc.description.degree | Master of Science | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:42445 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/124295 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | Creative Commons Attribution 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
| dc.subject | Proteomics | en |
| dc.subject | Mass spectrometry | en |
| dc.subject | Breast cancer | en |
| dc.subject | Secretome | en |
| dc.subject | Cell membrane | en |
| dc.subject | Brain metastasis | en |
| dc.subject | Tumor microenvironment | en |
| dc.subject | Intercellular communication | en |
| dc.title | Cancer Proliferation at the Brain Metastatic Site: A Proteomic Exploration of Inter-Cellular Cross-talk Sustained by Cell-membrane/Secretome Interactions | en |
| dc.type | Thesis | en |
| thesis.degree.discipline | Biological Sciences | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | masters | en |
| thesis.degree.name | Master of Science | en |
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