Joseph C. Loftus, Ph.D.

Integrin Signaling in Cell Migration and Growth

The capacity of cells to recognize other cells and specific elements of their surrounding extracellular matrix plays a central role in a diverse range of cellular processes including cellular differentiation, cell migration, the immune response, and the maintenance of tissue architecture. These adhesive interactions are mediated by a limited number of cell surface adhesion receptor families. Integrins are a family of cell surface heterodimeric glycoprotein receptors that mediate a host of cell-cell and cell-matrix interactions that underlie numerous pathophysiological processes. As the predominant receptors for extracellular matrix, integrin function provides a two-way flow of information between cells and their external environment as manifested by the capacity of integrin complexes to regulate both the assembly of an extracellular matrix and cellular behavior in response to ligand engagement. A primary focus of the research in the laboratory is the role of integrin-mediated adhesion and signaling in the regulation of cell migration and cell growth.

Specifically, we are investigating the role that integrin-mediated adhesion plays in the behavior of malignant brain tumors. Malignant glioblastomas are a leading cause of CNS tumor-related death. The biology of malignant glioma presents significant problems for successful treatment with the current regimen of surgery, radiotherapy, and chemotherapy. The aggressive local invasion of malignant cells from the original tumor into the surrounding normal brain effectively renders complete surgical resection impossible. Similarly, chemotherapy and ionizing radiation alone or in combination have produced only a modest increase in median survival due to the challenge of effectively targeting the invading cells and the innate resistance of a population of GBM cells to radio- and chemotherapeutic agents. Overall, the survival statistics for patients with malignant gliomas have not shown any significant improvement for the past 20 years, underscoring the importance for new insights into therapeutic approaches.

The characteristic feature of glioblastoma is the propensity of the malignant cells to invade the penumbral area of otherwise healthy brain. As such, interactions between parenchymal matrix proteins, surface adhesion receptors, and the cytoskeleton are integral to the invasion process. By linking the extracellular matrix to the internal cytoskeleton, integrins play a critical mechanical role in the migration of most cells. Moreover, integrin-mediated adhesion to extracellular matrix leads to the formation of the focal adhesion complex, a protein scaffold highly enriched in signaling effectors that affect cellular differentiation, proliferation, and migration. We have demonstrated that the related non-receptor tyrosine kinases FAK and Pyk2 are important effectors within the focal adhesion complex in the biology of malignant gliomas. Notably, increased expression of FAK increased glioma cell anchorage independent growth in vitro and increased tumor cell proliferation in vivo. Increased Pyk2 activity has been correlated with increased glioma cell migration/invasion in vitro. We have also demonstrated that silencing expression of Pyk2 or FAK or modulating endogenous Pyk2 activity significantly extends survival in animal models. Therefore we have hypothesized that the balance between FAK and Pyk2 activity and their differential regulation are determining factors in the temporal development of the proliferative or invasive phenotypes. The goal of our ongoing research is to define the molecular mechanisms that regulate the activity of these kinases and to identify their downstream effectors and the signaling pathways activated by these kinases. We are particularly interested in identifying protein-protein interactions that regulate kinase activity as an alternative to catalytic targeting. As proliferation and invasion are integral to the progression of the disease, greater insights into the molecular mechanisms that regulate these distinct cellular phenotypes are required for the development of novel therapeutic strategies to improve clinical outcome.