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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA142536-04
Application #
8627575
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$382,206
Indirect Cost
$122,145
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Pak, Ekaterina; Segal, Rosalind A (2016) Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy. Dev Cell 38:333-44
Bandopadhayay, Pratiti; Ramkissoon, Lori A; Jain, Payal et al. (2016) MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48:273-82
Yuzugullu, Haluk; Von, Thanh; Thorpe, Lauren M et al. (2016) NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov 2:16030
Stevens, Mark M; Maire, Cecile L; Chou, Nigel et al. (2016) Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate. Nat Biotechnol 34:1161-1167
Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane et al. (2016) Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas. Clin Cancer Res 22:1185-96
Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6
Filbin, Mariella G; Segal, Rosalind A (2015) How neuronal activity regulates glioma cell proliferation. Neuro Oncol 17:1543-4
Brastianos, Priscilla K; Carter, Scott L; Santagata, Sandro et al. (2015) Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov 5:1164-77
Zhou, Pengcheng; Erfani, Sonia; Liu, Zeyi et al. (2015) CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion. Oncotarget 6:29675-93
Zhao, Xuesong; Ponomaryov, Tatyana; Ornell, Kimberly J et al. (2015) RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer Res 75:3623-35

Showing the most recent 10 out of 50 publications