Medulloblastomas are the most common solid pediatric malignant tumors. These tumors arise in young children from dividing progenitor cells in the cerebellum. Current treatments for medulloblastoma, surgery, cranio-spinal radiation, and chemotherapy, leave survivors with life-long, devastating side effects. Moreover, medulloblastoma recurrence and metastasis are lethal. Development of new medulloblastoma therapies that are less debilitating and more effective has been hampered by poor understanding of the molecular and cell biological events causing the tumors and promoting their recurrence and metastasis. 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. Medulloblastomas are divided into 4-6 genetic subclasses. Approximately 30% of medulloblastomas are associated with a Sonic hedgehog (SHH) pathway genetic signature, and aberrant activation of this pathway promotes medulloblastoma in genetically engineered mouse models. Cerebellar granule neuron precursors (CGNPs) have been proposed as cells of origin for SHH medulloblastomas, and they depend on SHH for proliferation during development. In vitro, these cells (derived from neonatal mice) divide and differentiate much as they do in vivo, hence they are useful for studying how signaling pathways regulate proliferation during normal brain development and in medulloblastomas. Using such cultures and mouse models, we have found that Shh promotes activity of the oncogene YAP, which in turn drives expression of IGF2, contributing to enhanced proliferation and permitting tumor cells to survive radiation, which can lead to tumor recurrence and genomic instability. Importantly, we have shown that YAP and IGF2 are highly expressed in human SHH medulloblastomas. The studies described in the proposal "Hedgehog:YAP:IGF2/mTOR axis in cerebellar precursor division and medulloblastoma" focus on characterizing how these pathways interact to promote medulloblastoma growth and metastasis. These studies use primary CGNP cultures, analysis of wild-type and Shh medulloblastoma-bearing mice, and anonymized human patient samples to investigate how YAP regulates IGF2, whether IGF2 inhibition may be a viable therapeutic modality, determine the requirement for YAP in Shh medulloblastoma growth, recurrence, and metastasis, and test the hypothesis that hypoxia-inducible factor (HIF) lies downstream of Shh/IGF-mediated mTOR activation and plays critical roles in Shh mitogenic and oncogenic signaling. The long-term goal of these studies is to determine how modulating the function of Shh and IGF downstream effectors such as YAP and HIF might be a useful therapeutic approach to treat medulloblastomas and other cancers where these pathways are active.

Public Health Relevance

Medulloblastomas, the most common solid malignant pediatric tumor, arise in the developing brain of young children. These tumors are currently treated with surgery, cranio-spinal radiation, and chemotherapy. Survivors suffer devastating life-long side effects due to the damage these treatments do to the still developing brain, and metastasis and recurrence are lethal. The studies proposed in Hedgehog:YAP:IGF2/mTOR axis in cerebellar precursor division and medulloblastoma will investigate how molecules that promote proliferation and survival in the developing brain contribute to medulloblastoma formation, recurrence, and metastasis, and will test the hypothesis that such molecules are potential targets for therapeutic approaches 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 #
5R01NS061070-08
Application #
8517833
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Fountain, Jane W
Project Start
2007-09-30
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$329,307
Indirect Cost
$118,213
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Bhatia, Bobby; Potts, Chad R; Guldal, Cemile et al. (2012) Hedgehog-mediated regulation of PPARýý 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
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Parathath, Susana R; Mainwaring, Lori Anne; Fernandez-L, Africa et al. (2010) ýý-Arrestin-1 links mitogenic sonic hedgehog signaling to the cell cycle exit machinery in neural precursors. Cell Cycle 9:4013-24
Bhatia, Bobby; Malik, Arfa; Fernandez-L, Africa et al. (2010) p27(Kip1), a double-edged sword in Shh-mediated medulloblastoma: Tumor accelerator and suppressor. Cell Cycle 9:4307-14
Bhatia, Bobby; Nahle, Zaher; Kenney, Anna Marie (2010) Double trouble: when sonic hedgehog signaling meets TSC inactivation. Cell Cycle 9:456-9
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Bhatia, Bobby; Northcott, Paul A; Hambardzumyan, Dolores et al. (2009) Tuberous sclerosis complex suppression in cerebellar development and medulloblastoma: separate regulation of mammalian target of rapamycin activity and p27 Kip1 localization. Cancer Res 69:7224-34

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