The overall objective ofthis project is to develop a new understanding ofthe microenvironment that supports the growth, survival and migration of astrocytoma cells, and thereby identify new therapeutic approaches. In preliminary studies we have shown that human astrocytoma cells do not grow indiscriminately within the brain parenchyma, but prefer to grow in particular microenvironments. In the proposed studies we will use primary cultures from patient samples to determine whether astrocytomas are addicted to the environment of the brain region in which they developed, and to define cellular mechanisms by which the tumor microenvironment promotes tumor maintenance. We have three aims:
Aim One : Determine whether pediatric astrocytomas are "addicted" to the particular location in which they originated. We will use a new slice overiay assay, to determine whether i) forebrain tumors preferenfially grow in the specialized microenvironment of the forebrain;ii) hindbrain tumors preferentially grow in the cerebellum and brainstem areas ofthe hindbrain;iii) BRAF overexpression, a characteristic feature of cerebellar pilocytic astrocytomas, specifically facilitates growth of neural precursor in the cerebellar microenvironment.
Aim Two : Define the cellular basis ofthe microenvironment While the microenvironment is cleariy important for tumor growth and maintenance, the reason why tumor cells are preferentially found in particular locations is not understood. We will determine whether i) the microenvironment stimulates tumor proliferafion;ii) the microenvironment selectively promotes tumor cell survival;iii) tumor cells preferentially migrate towards this microenvironment.
Aim Three : Determine whether primary cilia coordinate the tumor cell response to its microenvironment. Our preliminary studies indicate that many astrocytoma samples exhibit primary cilia, visualized with antibodies to acetylated tubulin or adenylate cyclase 3. To determine whether primary cilia are signaling organelles that contribute to growth of astrocytomas, we will determine whether i) Primary cilia are preferenfially found on higher grade tumors;ii) Primary cilia point towards the vasculature;iii) components of crifical growth pathways localized to cilia of tumor cells;iv) Primary cilia are required for tumor growth.

Public Health Relevance

In cooperation with the Innovative Neuro Pathology (INP) Core and Projects One and Two, these studies on the tumor microenvironment will identify new therapeutic targets for treating pediatric brain tumors. Future therapies can then be developed that attack the interactions of the tumor and its microenvironment, an approach that may allow therapeutic efficacy with less damage to the normally developing brains of children.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Bechet, Denise; Gielen, Gerrit G H; Korshunov, Andrey et al. (2014) Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol 128:733-41
Francis, Joshua M; Zhang, Cheng-Zhong; Maire, Cecile L et al. (2014) EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 4:956-71
Fontebasso, Adam M; Papillon-Cavanagh, Simon; Schwartzentruber, Jeremy et al. (2014) Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46:462-6
Chudnovsky, Yakov; Kim, Dohoon; Zheng, Siyuan et al. (2014) ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state. Cell Rep 6:313-24
Bergthold, Guillaume; Bandopadhayay, Pratiti; Bi, Wenya Linda et al. (2014) Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta 1845:294-307
Sevenich, Lisa; Bowman, Robert L; Mason, Steven D et al. (2014) Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol 16:876-88
Liu, Xiaohui; Ide, Jennifer L; Norton, Isaiah et al. (2013) Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging. Sci Rep 3:2859
Stevens, Michael; Cheng, Jeffrey B; Li, Daofeng et al. (2013) Estimating absolute methylation levels at single-CpG resolution from methylation enrichment and restriction enzyme sequencing methods. Genome Res 23:1541-53
Ramkissoon, Lori A; Horowitz, Peleg M; Craig, Justin M et al. (2013) Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 110:8188-93
Katz, S G; Fisher, J K; Correll, M et al. (2013) Brain and testicular tumors in mice with progenitor cells lacking BAX and BAK. Oncogene 32:4078-85

Showing the most recent 10 out of 13 publications