Research Abstract:
The development of the mammalian brain is a highly regulated process involving both cell-autonomous and non-cell-autonomous decisions that determine cell fate, proliferation, migration and death. The genes that govern these critical decisions are often mutated in human cancers, and their de-regulated function in the central nervous system (CNS) leads to the development of brain tumors. Our laboratory is interested in understanding the key signals that control normal neural stem cell (NSC) and glial cell growth and differentiation in vitro and in vivo. To this end, we study the genes mutated in the two cancer predisposition syndromes, neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2), in which affected individuals develop brain tumors. We have generated numerous genetically-engineered mouse models to explore the relationship between developmental neurobiology (normal growth regulation in the brain) and neuro-oncology (brain tumor formation).
Our studies of the NF1 and NF2 tumor suppressor genes have elucidated several important growth regulatory pathways that dictate cell growth and differentiation in astrocytes (glia), neurons, and neural stem cells. We are currently studying how regulation of Ras signaling, mammalian target of rapamycin (mTOR) activity, and intracellular cyclic AMP generation controls cell proliferation, cell death, and differentiation in each of these cell types in the brain both in vitro and in vivo.
Similar to the developing brain, neoplastic cells receive cues from their local microenvironment that regulate cell proliferation. Using Nf1 mouse brain tumor models, we have identified both cellular and biochemical signals that emanate from the tumor microenvironment (stroma) to control tumor growth. Current studies are focused on determining how brain immune system cells (microglia) promote tumor cell proliferation as well as on identifying additional stromal patterning cues that dictate where and when tumors form in the brain.
Recent studies suggest that brain tumors may arise from cells with stem cell properties (cancer stem cells). To understand the relationship between normal neural stem cell function and tumorigenesis in the brain, we have developed several mouse models in which select tumor suppressor genes are inactivated in neuroglial progenitors. We are actively using these in vivo models in combination with in vitro systems to define the role of these genes and their downstream signaling pathways in governing cell fate decisions in the CNS.
Selected Publications:
Daginakatte GC, Gutmann DH. Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genetics 2007 16:1098-1112.
Hegedus B, Dasgupta B, Shin JE, Emnett RJ, Hart-Mahon EK, Elghazi L, Bernal-Mizrachi E, Gutmann DH. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell 2007 1:443-457 [cover feature].
Sandsmark DK, Zhang H, Hegedus B, Pelletier CL, Weber JD, Gutmann DH. Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-deficient astrocytes. Cancer Res 2007 67:4790-4799.
Sharma MK, Mansur DB, Reifenberger G, Perry A, Leonard JR, Aldape KD, Albin MG, Emnett RJ, Loeser S, Watson MA, Nagarajan R, Gutmann DH. Distinct genetic signatures among pilocytic astrocytomas related to their brain region origin. Cancer Res 2007 67:890-900.
Tang X, Jang S-W, Wang X, Liu Z, Bahr SM, Sun S-Y, Brat D, Gutmann DH, Ye K. Akt phosphorylation regulates merlin tumor suppressor activity by mediating merlin ubiquitination and degradation. Nature Cell Biology 2007 9:1199-1207.
Last Updated: 11/26/2007 |