Active Research Projects
Much of our research is focused on oligodendrocyte transcription factor (OLIG2)—a lineage-specific transcription factor that has been shown to be one of the core factors required for the proliferation of glioma stem-like cells. We have three ongoing projects in our laboratory:
Mechanisms that Trigger the Invasive Phenotype in Glioma Cells
One of the classifying characteristics of high-grade gliomas is the extensive infiltration of normal brain parenchyma by invasive tumor cells. A proposed explanation of this behavior, commonly called the go versus grow theory, suggests that tumor cells accomplish the aforementioned infiltration by specializing to either proliferate or migrate and invade.
We are interested in dissecting the intrinsic and extrinsic cellular mechanisms that trigger brain tumor cells to switch their function from proliferation to invasion and vice versa. We have found that the expression of the central nervous system-specific transcription factor OLIG2 can promote proliferation when it is phosphorylated at its N-terminus. In contrast, the glioma cells that express unphosphorylated OLIG2 are highly invasive. (Figs. 1 and 2)
Mechanistically, unphosphorylated OLIG2 induces transforming growth factor-beta 2 (TGFβ2) expression and promotes invasive mesenchymal properties in glioma cells. Inhibition of the TGFβ2 pathway blocks this OLIG2-dependent invasion1. (Fig. 1)
The role of OLIG2 in glioblastoma multiforme (GBM) invasion provides strong evidence for the presence of glioma stem-like cells at the invasive rim. The OLIG2+, therapy- resistant cells that evade surgical resection could be the likely source of tumor recurrence in GBM. Although therapies targeting glioma invasion alone have shown no clinical benefit, our data provide strong support for adjuvant therapies in conjunction with antiproliferative agents that can target invasive cells.
Several agents targeting the TGFβ pathway, including an antisense oligonucleotide against TGFβ2 (AP-12009), are currently being evaluated in clinical trials for high-grade gliomas. We are evaluating the efficacy of combination treatments with inhibitors of OLIG2 phosphorylation and the TGFβ2 pathway on GBM growth in murine models using patient-derived cells.
Growth Factor Signaling in Glioma Stem-like Cells
Aberrations in receptor tyrosine kinases (RTKs) are commonly found in glioblastomas. Either amplifications or gain of function mutations in the epidermal growth factor receptor (EGFR) gene are found in 40 to 50 percent of glioblastomas. In addition, almost 35 percent of these tumors have either amplifications or mutations in the platelet-derived growth factor alpha (PDGFRa) gene.
We have found that the OLIG2 protein forms a positive feedforward circuit with the receptor tyrosine kinase EGFR, the most commonly mutated oncogene in human brain tumors, to sustain co-expression2. Furthermore, loss of OLIG2 function results in a phenotypic shift from a stem profile to a more differentiated state in glioma cells. (Fig. 3) Our studies thereby provide insight into how co-option of a primitive developmental program by glioma cells can result in the aberrant expression of lineage-determining factors (i.e., OLIG2) to sustain their heterogeneity.
We are interested in determining the effects of common therapies on the stem cell population and their subtype identity within glioblasoma multiforme (GBM) tumors, with a long-term goal of identifying ideal combination therapies that can sensitize GBM tumors.
Identifying and Targeting Druggable Coregulator Proteins of OLIG2 for Malignant Glioma Therapy
OLIG2 is a basic helix loop helix (bHLH) transcription factor that plays an important role in sustaining the replication competence of neural progenitor cells in the embryo and in the postnatal brain. This promitogenic role of OLIG2 has a pathological correlate in malignant glioma.
We have shown that OLIG2 is expressed in almost all diffuse gliomas, adult as well as pediatric. Recent studies have shown that the highly tumorigenic and therapy-resistant subpopulation of glioma stem cells (GSCs) within gliomas is a potential source of resistance to therapy. We have demonstrated that OLIG2 is expressed in glioma stem/progenitor-like cells and is required for tumor formation in human xenograft models as well as in a genetically relevant murine model of glioma. (Fig. 4)
Recently, OLIG2 was identified as one of the four core transcription factors that are critical to the maintenance of the glioma stem cell state. Less tumorigenic differentiated glioma cells, when transduced with these four transcription factors, could be reprogrammed to highly tumorigenic GSCs. OLIG2 is the only factor that can impart this tumorigenic potential.
Given the fact that OLIG2 is only expressed in the central nervous system (CNS), and that selective inhibition of OLIG2 in the adult brain is survivable for extended periods of time, identifying tumor-specific interactions of pOLIG2/OLIG2 provides a unique opportunity for developing highly targeted therapies.
To that end, we are collaborating with Dr. Joshua LaBaer’s group at Arizona State University to identify direct interactors of OLIG2 using the Nucleic Acid Programmable Protein Arrays (NAPPA).
This project is funded by NIH/NINDS R01 Research Project Grant awarded to Dr. Mehta.
- Singh SK, Fiorelli R, Kupp R, Rajan S, Szeto E, Lo Cascio C, Maire CL, Sun Y, Alberta JA, Eschbacher JM, Ligon KL, Berens ME, Sanai N, Mehta S. Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway. Cell Rep. 2016 Jul 26;16(4):950-66.
- Kupp R, Shtayer L, Tien AC, Szeto E, Sanai N, Rowitch DH, Mehta S. Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells. Cell Rep. 2016 Sep 13;16(11):2838-45.
Shwetal Mehta, PhD
Laboratory of Glial Tumor Biology
Email: [email protected]
Office: (602) 406-3288