PhD – The Johns Hopkins University, Baltimore, Maryland
The laboratory is focused on elucidating the mechanisms driving diffuse high-grade glioma (HGG) in children. In children and adults, diffuse high-grade gliomas (HGGs), including Grade III anaplastic astrocytomas and Grade IV glioblastomas, share a devastating outcome, with median survival slightly greater than one year, and five-year survival of 10-25%. Although HGGs from different age groups share related gene expression signatures, histopathological features, and frequent mutations in common pathways, there are a number of distinguishing features of pediatric HGG that indicate a unique pathogenesis. While adult glioblastomas arise predominantly in the cerebral cortex, in children, a broader spectrum of anatomical locations are more frequently involved, including the occurrence of diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem.
Recent genome-wide studies from our group and others provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation as well as developmental signaling pathways. It is now clear that there are at least several distinct subgroups of pediatric diffuse HGG based on clinical features and recurrent mutations. Ongoing work is directed towards integrating the latest genomic findings from primary human tumors to develop improved models of these disease subgroups that recapitulate the genetic and biological features of the disease for mechanistic studies and preclinical testing of selective therapies.
Jones C, Baker SJ. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nature Reviews Cancer Oct;14(10), 2014.
Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, Zhu X, Qu C, Chen X, Zhang J, Easton J, Edmonson M, Ma X, Lu C, Nagahawatte P, Hedlund E, Rusch M, Pounds S, Lin T, Onar-Thomas A, Heuther R, Kriwacki R, Parker M, Gupta P, Becksfort J, Wei L, Mulder HL, Boggs K, Vadodaria B, Yergeau D, Russell JC, Ochoa K, Fulton RS, Fulton LL, Jones C, Boop FA, Bronsicer A, Wetmore C, Gajjar A, Ding L, Mardis ER, Wilson RK, Taylor MR, Downing JR, Ellison DW, Zhang J, Baker SJ. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444-50, 2014.
Diaz AK, Baker SJ. The genetic signatures of pediatric high-grade glioma: no longer a one-act play.Semin Radiat Oncol 24:240-247, 2014.
Huether R, Dong L, Chen X, Wu G, Parker M, Wei L, Ma J, Edmonson MN, Hedlund EK, Rusch MC, Shurtleff SA, Mulder HL, Boggs K, Vadordaria B, Cheng J, Yergeau D, Song G, Becksfort J, Lemmon G, Weber C, Cai Z, Dang J, Walsh M, Gedman AL, Faber Z, Easton J, Gruber T, Kriwacki RW, Partridge JF, Ding L, Wilson RK, Mardis ER, Mullighan CG, Gilbertson RJ, Baker SJ, Zambetti G, Ellison DW, Zhang J, Downing JR. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun 5:3630, 2014.
Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, Orisme W, Punchihewa C, Parker M, Qaddoumi I, Boop FA, Lu C, Kandoth C, Ding L, Lee R, Huether R, Chen X, Hedlund E, Nagahawatte P, Rusch M, Boggs K, Cheng J, Becksfort J, Ma J, Song G, Li Y, Wei L, Wang J, Shurtleff S, Easton J, Zhao D, Fulton RS, Fulton LL, Dooling DJ, Vadodaria B, Mulder HL, Tang C, Ochoa K, Mullighan CG, Gajjar A, Kriwacki R, Sheer D, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Baker SJ, Ellison DW. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45:602-12, 2013.
Paugh BS, Zhu X, Qu C, Endersby R, Diaz AK, Zhang J, Bax DA, Carvalho D, Reis RM, Onar-Thomas A, Broniscer A, Wetmore C, Zhang J, Jones C, Ellison DW, Baker SJ. Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas. Cancer Res 73:6219-29, 2013.
Zhu G, Chow LM, Bayazitov IT, Tong Y, Gilbertson RJ, Zakharenko SS, Solecki DJ, Baker SJ. Pten deletion causes mTorc1-dependent ectopic neuroblast differentiation without causing uniform migration defects. Development 139:3422-31, 2012.
Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, Olson JM, Geyer JR, Chi SN, da Silva NS, Onar-Thomas A, Baker JN, Gajjar A, Ellison DW, Baker SJ. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29(30):3999-4006, 2011.
Endersby R, Zhu X, Hay N, Ellison DW, Baker SJ. Nonredundant functions for Akt isoforms in astrocyte growth and gliomagenesis in an orthotopic transplantation model. Cancer Res 71(12):4106-16, 2011.
Chow LM, Endersby R, Zhu X, Rankin S, Qu C, Zhang J, Broniscer A, Ellison DW, Baker SJ. Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain. Cancer Cell 19(3):305-16, 2011.
Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D, Lowe J, Gajjar A, Zhao W, Broniscer A, Ellison DW, Grundy RG, Baker SJ. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28(18):3061-3068, 2010.
Broniscer A, Baker JN, Baker SJ, Chi SN, Geyer JR, Morris EB, Gajjar A. Prospective collection of tissue samples at autopsy in children with diffuse intrinsic pontine glioma. Cancer 116(19):4632-4637, 2010.
Chalhoub N, Zuo G, Zuo , Baker SJ. Cell-type specificity of PI3K signaling in Pdk1- and Pten-deficient brain. Genes Dev 23(14):1619-1624, 2009.
Frappart P-O, Lee Y, Russell HR, Chalhoub N, Wang Y-D, Orii KE, Zhao J, Kondo N, Baker SJ,McKinnon PJ. Genetic Alterations in medulloblastoma from mice with defective DNA double strand break repair. Proc Natl Acad Sci USA 106:1880-1885, 2009.
Chalhoub N, Baker SJ. PTEN and the PI3K Signaling Pathway in Cancer. Annu Rev Pathol 4:127-150, 2009.
Endersby R, Baker SJ. PTEN Signaling in Brain: Neuropathology and Tumorigenesis. Oncogene 27:5416-5430, 2008.
Chow LML, Zhang J, Baker SJ. Inducible Cre recombinase activity in mouse mature astrocytes and adult neural precursor cells. Transgenic Research 17:919-928, 2008.
Fraser MM, Bayazitov IT, Zakharenko SS, Baker SJ. Pten deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience 151:476-488, 2008.
Broniscer A, Baker SJ, West AN, Fraser MM, Proko E, Kocak M, Dalton J, Zambetti GP, Ellison DW, Kun LE, Gajjar A, Gilbertson RJ, Fuller CE. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol 25:682-689, 2007.
Baker SJ. PTEN Enters the Nuclear Age. Cell 128:125-8, 2007.
Chow LM, Tian Y, Weber T, Corbett M, Zuo J, Baker SJ. Inducible Cre recombinase activity in mouse cerebellar granule cell precursors and inner ear hair cells. Dev Dyn 11:2991-8, 2006.
Chalhoub N, Kozma SC, Baker SJ. S6k1 is not required for Pten-deficient neuronal hypertrophy.Brain Res 1100:32-41, 2006.
Kwon C-H, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ, Parada LF. Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377-388, 2006.
Chow LM, Baker SJ. PTEN function in normal and neoplastic growth. Cancer Lett 241:184-196, 2006.
Abel TW, Baker SJ, Fraser MM, Tihan T, Nelson JS, Yachnis A, Bouffard J, Mena H, Burger PC, Eberhart CG. Lhermitte-Duclos Disease: a Report of 31 Cases with Immunohistochemical Analysis of the PTEN/AKT/mTOR Pathway. J Neuropathol Exp Neurol 64:341-349, 2005.
Fraser MM, Zhu X, Kwon C-H, Uhlman EJ, Bajenaru ML, Gutmann DH, Baker SJ. Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res 64:7773-7779, 2004.
Baker SJ, McKinnon PJ. Tumour-suppressor function in the nervous system. Nat Rev Cancer 4:184-96, 2004.
Kwon CH, Zhu X, Zhang J, Baker SJ. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc Natl Acad Sci USA 100:12923-8, 2003.
Kwon CH, et al. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease.Nat Genet 29:404-11, 2001.
Last update: September 2014