The overall goal of research in my laboratory is to investigate the mechanism by which the unique brain microenvironment modulates the development and progression of primary and metastatic brain tumors. In particular, we are interested in exploring the role of astrocytes, a major class of glial cells. In response to diverse forms of CNS injury, astrocytes commonly undergo a phenotypic transformation with changes in morphology and in their expression of a wide range of signaling molecules. This pathologic process is referred to as reactive astrogliosis. Recently, we have shown that reactive astrocytes respond to gliomagenesis by expressing the signaling molecule sonic hedgehog (SHH). These altered astrocytes reside in two main locations: in the perviascular region that represents stem cell niches, and along the border of the tumor mass. We are interested in studying the mechanism and functional consequences of astrocyte activation in primary and metastatic brain tumors in their intact microenvironment. One focus is to understand the role of SHH-Gli signaling pathway in primary and metastatic brain tumors. To best replicate the situation of human glioma formation and growth, we use a genetically engineered mouse model of brain tumors driven by RCAS/tv-a, a somatic cell specific gene transfer. To study the functional role of components of microenvironment we use genetically engineered, conditionally activated mouse models. Better understanding of tumor-microenvironment interactions in the brain will likely contribute to improved clinical therapies for primary and metastatic brain tumors.
Amankulor, N. M., Hambardzumyan, D., Pyonteck, S. M., Becher, O. J., Joyce, J. A., and Holland, E. C. (2009). Sonic hedgehog pathway activation is induced by acute brain injury and regulated by injury-related inflammation. J Neurosci 29, 10299-10308.
Hambardzumyan, D., Amankulor, N. M., Helmy, K. Y., Becher, O. J., and Holland, E. C. (2009a). Modeling Adult Gliomas Using RCAS/t-va Technology. Transl Oncol 2, 89-95.
Hambardzumyan, D., Becher, O. J., Rosenblum, M. K., Pandolfi, P. P., Manova-Todorova, K., and Holland, E. C. (2008). PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22, 436-448.
Podsypanina, K., Du, Y. C., Jechlinger, M., Beverly, L. J., Hambardzumyan, D., and Varmus, H. (2008). Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321, 1841-1844.
Lerner Research Institute
Mail Code NB21
9500 Euclid Avenue
Cleveland, Ohio 44195