Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit large cell/anaplastic (LCA) histology usually fail therapy and die from their disease. Improved approaches to treating these patients are likely to come from a deeper understanding of LCA tumors, including their aggressive growth properties and their invasive and metastatic behavior. Unfortunately, human LCA MB tissue is difficult to obtain, and existing genetically engineered mouse (GEM) models of MB rarely display anaplasia or metastasis. To address this problem, we have collected >100 human LCA MBs, including paired samples of primary/metastatic tumors. In addition, we have generated GEM and transplant-based models of LCA MB, and mobilized the transposable element Sleeping Beauty (SB) to promote anaplasia and metastasis in these models. Through analysis of our human and murine datasets, we propose to identify the cells and genes that drive progression in LCA medulloblastoma. This application brings together investigators from three institutions, with collective experience in neural development, stem cell biology and genomics of both human and murine MB. Our complementary backgrounds and expertise uniquely position us to investigate the cellular and molecular basis of LCA MB, and will ultimately allow us to develop more effective approaches to targeting these aggressive tumors.
The proposed studies focus on large cell/anaplastic medulloblastoma, a highly malignant pediatric brain tumor with an extremely poor prognosis. By identifying the cells and genes responsible for the aggressive behavior of this tumor, we hope to develop more effective approaches to therapy.
| Zapotocky, Michal; Mata-Mbemba, Daddy; Sumerauer, David et al. (2018) Differential patterns of metastatic dissemination across medulloblastoma subgroups. J Neurosurg Pediatr 21:145-152 |
| Mack, Stephen C; Pajtler, Kristian W; Chavez, Lukas et al. (2018) Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553:101-105 |
| Guerreiro Stucklin, Ana S; Ramaswamy, Vijay; Daniels, Craig et al. (2018) Review of molecular classification and treatment implications of pediatric brain tumors. Curr Opin Pediatr 30:3-9 |
| Wang, Yang; Li, Yue; Yue, Minghui et al. (2018) N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications. Nat Neurosci 21:195-206 |
| Cavalli, Florence M G; Hübner, Jens-Martin; Sharma, Tanvi et al. (2018) Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136:227-237 |
| An, Zhenyi; Aksoy, Ozlem; Zheng, Tina et al. (2018) Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene 37:1561-1575 |
| Bertrand, Kelsey C; Faria, Claudia C; Skowron, Patryk et al. (2018) A functional genomics approach to identify pathways of drug resistance in medulloblastoma. Acta Neuropathol Commun 6:146 |
| Waszak, Sebastian M; Northcott, Paul A; Buchhalter, Ivo et al. (2018) Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19:785-798 |
| Garzia, Livia; Kijima, Noriyuki; Morrissy, A Sorana et al. (2018) A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. Cell 172:1050-1062.e14 |
| Wang, Jun; Garancher, Alexandra; Ramaswamy, Vijay et al. (2018) Medulloblastoma: From Molecular Subgroups to Molecular Targeted Therapies. Annu Rev Neurosci 41:207-232 |
Showing the most recent 10 out of 77 publications
