Breast cancer is the most common cancer type in women that frequently spreads. In 30-40% of patients with advancing breast cancer, the disease will metastasize to the brain and not respond to current therapies. Despite advances in early detection and treatment of primary breast cancer and lesions outside the brain, breast cancer brain metastasis is uniformly fatal. The proposed studies bring together genetic and orthotopic models to examine mechanisms that control vascular integrity as a regulator of breast cancer brain metastasis. Between the Eliceiri and Felding labs, we will use defined genetic and therapeutic models to target the pathophysiological relevance of vascular leak, vascular normalization and the contribution of platelets to the initiation, growth and invasion of brain metastatic lesions. Our experimental design exploits the complementary and innovative approaches developed in our laboratories to investigate specific mediators of vascular normalization in breast cancer brain metastasis. The unique focus of our collaboration will challenge the dogma of vascular normalization in defined genetic host models of breast cancer brain colonization and progression of metastatic lesions. The unmet need and specific challenge of this proposal is to deploy advances developed in our groups and examine contributions of src kinase, endothelial focal adhesion kinase (FAK), and platelet functions to mediate cerebral vascular integrity in brain metastasis. We will use unique bioluminescence models to assess peri-vascular astrocyte and microglial activation, signaling mediated by extracellular matrix components, and candidate therapeutics that support the findings from our genetic models.
Aim 1 will determine the role of Src-mediated vascular permeability in the host compartment during breast cancer brain metastasis.
Aim 2 will show whether an increase in vascular normalization through endothelial- specific deletion of FAK protects the brain from breast cancer metastasis.
Aim 3 will determine how platelets affect brain metastasis and endothelial integrity of the blood brain barrier. These experiments will provide a functional basis for a better understanding of mechanisms through which cerebral vascular normalization controls breast cancer brain metastasis. The results may validate src, endothelial FAK and specific platelet functions as key targets for prevention and treatment of brain metastasis in breast cancer patients.
Breast cancer is the most common cancer in women that frequently spreads. In more than one third of women with advancing breast cancer, the disease will spread to the brain and not respond to current therapies;despite advances in early detection and treatment of primary breast cancer and lesions outside the brain, the mortality in patients with brain metastatic breast cancer is extremely high. We propose to define mechanisms that regulate the permeability of the blood brain barrier, where circulating breast cancer cells must penetrate to colonize the brain.
| Tat, John; Loriot, Céline; Henze, Martha et al. (2017) CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues. Oncotarget 8:114911-114923 |
| Baird, Andrew; Coimbra, Raul; Dang, Xitong et al. (2016) Up-regulation of the human-specific CHRFAM7A gene in inflammatory bowel disease. BBA Clin 5:66-71 |
| Wold, Erik D; Smider, Vaughn V; Felding, Brunhilde H (2016) Antibody Therapeutics in Oncology. Immunotherapy (Los Angel) 2: |
| Baird, Andrew; Costantini, Todd; Coimbra, Raul et al. (2016) Injury, inflammation and the emergence of human-specific genes. Wound Repair Regen 24:602-6 |
| Weber, Martin R; Zuka, Masahiko; Lorger, Mihaela et al. (2016) Activated tumor cell integrin ?v?3 cooperates with platelets to promote extravasation and metastasis from the blood stream. Thromb Res 140 Suppl 1:S27-36 |
| Costantini, Todd W; Meads, Morgan; Dang, Xitong et al. (2016) The Response to Burn Injury in Mice With Human Hematolymphoid Systems. Ann Surg 263:199-204 |
| Baird, Andrew; Deng, Chenliang; Eliceiri, Matthew H et al. (2016) Mice engrafted with human hematopoietic stem cells support a human myeloid cell inflammatory response in vivo. Wound Repair Regen 24:1004-1014 |
| Kurczy, Michael E; Zhu, Zheng-Jiang; Ivanisevic, Julijana et al. (2015) Comprehensive bioimaging with fluorinated nanoparticles using breathable liquids. Nat Commun 6:5998 |
| Johnson, Caroline H; Dejea, Christine M; Edler, David et al. (2015) Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab 21:891-7 |
| Torbett, Bruce E; Baird, Andrew; Eliceiri, Brian P (2015) Understanding the rules of the road: proteomic approaches to interrogate the blood brain barrier. Front Neurosci 9:70 |
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