The McCarty laboratory uses genetically engineered animal models, primary cell culture systems, and human tissue samples to study adhesion and signaling pathways that regulate brain development and cancer. In particular, we study how integrins and their extracellular matrix (ECM) protein ligands mediate bi-directional communication between glial cells or glioma cells and blood vessels in the brain microenvironment.
The billions of neurons and glial cells in the CNS are intertwined with a complex web of blood vessels. These various cell types dynamically interact with each other to form integrated complexes, or neurovascular units, that regulate the structural and functional integrity of the brain and have causative links to many brain pathologies.
One integrin, alphaVbeta8, which is expressed in perivascular neural cells and brain tumor cells, is of particular interest. This integrin is a receptor for latent TGFbeta's (LAP-TGFbetas), which are expressed by cells as inactive ECM-associated complexes. Genetic ablation of alphaVbeta8 integrin in neural cells or TGFbeta signaling components in endothelial cells lead to strikingly similar developmental neurovascular defects, including abnormal brain angiogenesis, hemorrhage and premature death.
Hence, alphaVbeta8 integrin and latent TGFbetas are components of an adhesion and signaling axis that link perivascular neural cells, vascular basement membranes and cerebral endothelial cells during development. alphaVbeta8 integrin is unregulated in the malignant brain cancer glioblastoma (GBM) and tumor cells co-opt this pathway to promote pathological angiogenesis and perivascular tumor cell invasion.
Current efforts in the lab involve characterizing integrin-regulated intracellular signaling pathways that drive cell invasion, characterizing novel ECM protein ligands, and identifying other signaling pathways that cross-talk with alphaVbeta8 integrin during brain development and cancer.