Medulloblastomas are the most common solid pediatric malignant tumors. These tumors arise in young children from dividing progenitor cells in the cerebellum, a brain region which develops after birth. The current treatments for medulloblastoma surgery, cranio-spinal radiation, and chemotherapy leave survivors with life-long, devastating side effects, including movement and cognitive disorders, seizures, psychiatric problems, and risk of other tumors due to radiation. These effects can be attributed to the inability of the treatments to preferentially target the tumor cells and spare the rest of the brain. Development of new medulloblastoma therapies that are more tumor-cell specific has been hampered by a lack of understanding of the molecular events causing the tumors and the cell biological events that promote their initiation and growth. Greater insight into how genes and proteins regulate proliferation in cerebellar progenitor cells, and how their dys-regulation contributes to tumorigenesis, will identify targets for new therapies that can specifically affect tumor growth without damaging the still-developing brain. Signal transduction pathways that regulate cerebellar progenitor cell division have been associated with medulloblastomas in humans and in mouse models. The pathways activated by the secreted ligands Sonic hedgehog (Shh) and insulin-like growth factor (IGF) are particularly important for cerebellar progentior cell proliferation, and their activity is increased in medulloblastomas. Primary cultures of proliferating mouse cerebellar progenitor cells have genetic profiles similar to those of human medulloblastomas, and they depend on Shh and IGF signaling for proliferation. In culture, these cells divide and differentiate much as they do in vivo, indicating that they are useful for studying how signaling pathways regulate proliferation during normal brain development and in medulloblastomas. The studies described in the proposal """"""""Sonic hedgehog:Insulin-like growth factor cooperation in proliferating neural precursors"""""""" focus on characterizing how these pathways converge on a common target, insulin receptor substrate 1 (IRS1), to ultimately regulate translation of mRNAs into protein, an essential process for cell cycle progression during development and in cancer. These studies use primary cerebellar progenitor cultures and analysis of wild-type and IRS1-null mice to investigate how Shh regulates IRS1, how IRS1 functions in the developing cerebellum, and how the mRNA translation pathway component eIF4E, a downstream effector of IRS1, regulates new protein synthesis in cerebellar progenitors. The long- term goal of these studies is to determine how modulating the function of Shh and IGF downstream effectors such as IRS1 and eIF4E might be a useful therapeutic approach to treat medulloblastomas and other cancers where these pathways are operative, such as skin, prostate, and adult brain tumors.Medulloblastomas, the most common solid pediatric tumor, arise in the developing brain of young children. These tumors are currently treated with surgery radiation, and chemotherapy. Survivors suffer devastating life-long side effects due to the damage these treatments do to the still-developing brain. The studies proposed in 'Sonic hedgehog:Insulin-like growth factor cooperation in proliferating neural precursors'will shed light on how molecules that regulate cell division in immature neurons contribute to medulloblastoma formation and growth, and whether those molecules are potential targets for future treatments that will be less harmful to patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS061070-05
Application #
8064368
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Fountain, Jane W
Project Start
2007-09-30
Project End
2012-07-31
Budget Start
2011-05-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$300,655
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Malhotra, Anshu; Dey, Abhinav; Prasad, Niyathi et al. (2016) Sonic Hedgehog Signaling Drives Mitochondrial Fragmentation by Suppressing Mitofusins in Cerebellar Granule Neuron Precursors and Medulloblastoma. Mol Cancer Res 14:114-24
Dey, A; Robitaille, M; Remke, M et al. (2016) YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells. Oncogene 35:4256-68
Wen, J; Lee, J; Malhotra, A et al. (2016) WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma. Oncogene 35:5552-5564
Fernandez-L, A; Squatrito, M; Northcott, P et al. (2012) Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene 31:1923-37
Lee, Hae Young; Angelastro, James M; Kenney, Anna Marie et al. (2012) Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells. Dev Neurobiol 72:789-804
Guldal, Cemile G; Ahmad, Adiba; Korshunov, Andrey et al. (2012) An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation. Acta Neuropathol 123:573-86
Northcott, Paul A; Shih, David J H; Peacock, John et al. (2012) Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488:49-56
Bhatia, Bobby; Potts, Chad R; Guldal, Cemile et al. (2012) Hedgehog-mediated regulation of PPAR? controls metabolic patterns in neural precursors and shh-driven medulloblastoma. Acta Neuropathol 123:587-600
Bhatia, B; Hsieh, M; Kenney, A M et al. (2011) Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma. Oncogene 30:410-22
Mainwaring, L A; Kenney, A M (2011) Divergent functions for eIF4E and S6 kinase by sonic hedgehog mitogenic signaling in the developing cerebellum. Oncogene 30:1784-97

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