The overall objective of this 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 overlay assay, to determine whether i) forebrain tumors preferentially 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 clearly 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 proliferation;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 preferentially found on higher grade tumors;ii) Primary cilia point towards the vasculature;iii) components of critical growth pathways localized to cilia of tumor cells;iv) Primary cilia are required for tumor growth.
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.
|Filbin, Mariella G; Tirosh, Itay; Hovestadt, Volker et al. (2018) Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science 360:331-335|
|Zhou, Jing; Tien, An-Chi; Alberta, John A et al. (2017) A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. Cell Rep 18:3167-3177|
|Zhang, Jing; Gao, Xueliang; Schmit, Fabienne et al. (2017) CRKL Mediates p110?-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep 20:549-557|
|Ramkissoon, Shakti H; Bandopadhayay, Pratiti; Hwang, Jaeho et al. (2017) Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors. Neuro Oncol 19:986-996|
|Sun, Yu; Alberta, John A; Pilarz, Catherine et al. (2017) A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol 19:774-785|
|Zhao, Xuesong; Pak, Ekaterina; Ornell, Kimberly J et al. (2017) A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors. Cancer Discov 7:1436-1449|
|Ni, Jing; Xie, Shaozhen; Ramkissoon, Shakti H et al. (2017) Tyrosine receptor kinase B is a drug target in astrocytomas. Neuro Oncol 19:22-30|
|Ilic, Nina; Birsoy, K?vanç; Aguirre, Andrew J et al. (2017) PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proc Natl Acad Sci U S A 114:E3434-E3443|
|Pak, Ekaterina; Segal, Rosalind A (2016) Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy. Dev Cell 38:333-44|
|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|
Showing the most recent 10 out of 59 publications