Glioma, the most common primary brain tumor, remains incurable. Developing effective treatments depends on a better understanding of relevant cellular programs responsible for generating these tumors. An emerging concept in cancer research contends that activation of proliferative cellular processes is insufficient to cause tumor progression without concomitant suppression of apoptosis. The primary objective of this research proposal is to investigate the contribution of anti-apoptotic genes on the initiation, maintenance, and progression of glioma. Genes in the Signal Transducer and Activator of Transcription (STAT) signaling pathway are overexpressed in glioma and this pathway is a central hub of multiple cellular programs relevant to gliomagenesis including apoptotic suppression. The STAT3 gene, in particular, is associated with the aggressive mesenchymal subtype of glioma. Our hypothesis is that apoptotic suppression mediated by the STAT signaling pathway plays a causal role in the inexorable malignant progression of glioma. We will test this hypothesis by expressing genes in the STAT signaling axis in vivo to elucidate the effects of STAT pathway activation on glioma progression. Currently, most research evaluating gene overexpression in vivo is performed with xenograft models in immunodeficient mice that fail to recapitulate the microenvironment of brain tumors. These models use tumors formed by the implantation of fully malignant cells, rather than arising from a transformational event in a normal cell, thus obscuring analysis of the impact of a gene on the critical stages a tumor must overcome during its evolution. To study how anti-apoptotic genes affect tumor development we will employ a method of somatic cell transfer using the RCAS/tv-a system. This model permits the study of gene expression on endogenous tumor formation from its putative cell of origin in an immunocompetent mouse. Importantly, this model can be used to study the effect of immunosuppression on glioma progression as tumor-induced immunosuppression is mediated by STAT signaling. Our preliminary studies indicate that the anti-apoptotic genes in the STAT signaling pathway (including Bcl-2 and STAT3) enhance tumor formation, decrease survival, facilitate immunosuppressive intra-tumoral macrophages, and increase malignant progression by inducing necrosis - the hallmark of high-grade glioma. To investigate the impact of anti-apoptotic signaling programs and characterize their function, genes in the STAT signaling axis will be expressed using the RCAS/tv-a system. Specifically, we will investigate the roles of the Bcl2 (Specific Aim 1) and STAT gene families (Specific Aim 2) on tumor formation and progression. We expect to discover their contribution to the malignant degeneration of glioma and their promotion of tumor- induced immunosuppression. Ultimately, our results will help define therapeutic targets for glioma and the model will be used to test novel therapeutics against this deadly disease.

Public Health Relevance

Understanding the relevant genetic aberrations that contribute to brain cancer is critical for developing new therapies for this deadly disease. The signal transducers and activators of transcription (STAT) pathway is a regulator of multiple cellular processes critical to brain tumor formation. We will study the effect of STAT signaling on brain tumor initiation and progression and test novel therapeutics against this pathway with a unique mouse model that recapitulates critical features of the human disease.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS070928-04
Application #
8693033
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Fountain, Jane W
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Hospitals
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
Gressot, Loyola V; Doucette, Tiffany A; Yang, Yuhui et al. (2015) Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB-dependent proneural glioma model by suppressing apoptosis. Int J Cancer 136:2047-54
Schrand, Brett; Berezhnoy, Alexey; Brenneman, Randall et al. (2014) Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. Cancer Immunol Res 2:867-77
Doucette, Tiffany; Latha, Khatri; Yang, Yuhui et al. (2014) Survivin transcript variant 2 drives angiogenesis and malignant progression in proneural gliomas. Neuro Oncol 16:1220-8
Wei, Jun; Wang, Fei; Kong, Ling-Yuan et al. (2013) miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res 73:3913-26
Bhat, Krishna P L; Salazar, Katrina L; Balasubramaniyan, Veerakumar et al. (2011) The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25:2594-609
Doucette, Tiffany; Rao, Ganesh; Yang, Yuhui et al. (2011) Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv-a glioma model. Neoplasia 13:716-25