Abnormalities of neural stem/progenitor cell proliferation and differentiation are responsible for the majority of human brain tumors and a broad range of neurologic diseases. However, the specific transcriptional networks controlling stem/progenitor cell growth in normal cells and neurologic cancer are poorly understood. To address this area, my lab research has been directed towards identifying the transcription factor networks that control these processes, and elucidating their function using techniques in mouse genetics, translational human research, and molecular neuropathology.
The bHLH transcription factors Olig1 and Olig2 are essential for development of embryonic neural stem/progenitor cells into oligodendrocytes and specific types of neurons. However, the roles of these factors in later development have not been as extensively studied. Using mouse genetic studies, we have been able to demonstrate novel roles for these genes in adult brain progenitors such as NG2 cells, Type C cells of the subventricular zone (SVZ), and CD133 expressing cells. We are also studying roles for these factors in development of cholinergic neurons, cortical interneurons, and glia through analysis of newly constructed conditional mouse transgenic lines. Further investigation of these later stage roles are important for proper development of stem cell based therapies directed at diseases such as multiple sclerosis, and traumatic CNS injury.
Another major focus of the lab is the study of human CNS tumors. Malignant gliomas are one of the most lethal forms of human cancer. The cellular origins of gliomas are not known, but development from neural stem/progenitor cells or mature glial cells has been hypothesized. Using expression profiling and in vivo validation, our work has shown that human gliomas are characterized by high-level expression of multiple neural stem/progenitor transcription factors, including OLIG2, and not mature glial markers. Further studies by our group identified OLIG2 as a universal marker of human gliomas and the most reliable clinical biomarker of these cancers. Functional testing has also shown that OLIG2 is required for glioma development from neural stem cells and acts by directly inhibiting expression of the tumor suppressor gene, p21. This work therefore suggests that OLIG2 is a key lineage dependent therapeutic target in human gliomas.
Additional research efforts in the lab seek to systematically discover additional progenitor cell transcription factor networks critical for normal neural development and multiple CNS cancers. By combining integrative genomics and mouse genetics we have successfully identified transcription factors expressed in embryonic stem cell, astrocyte, pineal, and retinal progenitor cell development. We have validated that such factors represent lineage-restricted biomarkers of normal cell types and their corresponding cancers such as CNS germ cell tumors, astrocytoma, pineoblastoma, and retinoblastoma. Currently, we are determining whether mutation of these factors contributes to oncogenesis through copy number alterations (array CGH), point mutation (sequencing) or structural rearrangement (transcriptomic synthesis sequencing). Testing the function of these factors in human glioma cancer stem cells and mouse models is being performed to investigate their roles in oncogenesis. Identification of these factors will greatly aid development of molecular pathology tools that will advance the diagnosis, prognosis, and therapy of brain tumors and other diseases.
Translational pathology research and personalized medicine
In addition to basic studies in development and cancer biology, the lab has numerous projects in translational research which have a direct impact on human cancers of the brain. The Ligon lab directs the DFCI/BWH Living Tissue Bank which derives primary brain tumor cancer stem cell lines and xenografts from a wide range of patients as a mechanism for study of individual patient tumor properties. We are currently investigating the ability of these cells to serve as a personalized model of patient response to treatment and targeted therapeutics through advanced preclinical studies in mice. These studies are also being incorporated into clinical trials of experimental therapeutic agents to determine the next promising drugs for treatment of glioblastoma and other brain tumors.
Additional projects include development of exciting new biomarkers of cancer for diagnosis and prognostic prediction in human brain tumors. These studies include evaluation of stem cell transcription factors such as OLIG2, SOX2, and CRX. Additional work focuses on translation of research testing into real world clinical (CLIA certified) tests through collaborations with the BWH Center for Molecular Diagnostics and the DFCI Center for Molecular Oncologic Pathology. Past tests which the lab has developed include IHC for OLIG2, CRX, SOX2, and NANOG in various human cancers, novel FISH and array CGH testing for diganosis of pediatric pilocytic astrocytomas harboring duplication the tyrosine kinase BRAF, and development of a CLIA-certified sequencing test for v600e mutations in BRAF helpful in the diagnosis of ganglioglioma and other non-pilocytic gliomas.