Understanding epigenetics and cell fate in gliomagenesis
Molecular classifications of GBMs have shown that two major subtypes, termed Proneural (PN) and Mesenchymal (MES). Patients whose tumors exhibit a PN signature exhibit significantly improved overall survival compared to those of the MES subtype. Importantly, most IDH mutant, low grade gliomas also exhibit a PN gene enrichment pattern and better survival rates.
It is noteworthy that a MES transdifferentiation coupled with a loss of PN features either during tumor evolution or during recurrence is a bad prognosis for glioma patients and a PN to MES switch directly contributes to treatment resistance. Therefore suppressing the MES phenotype and restoration of the PN cellular fate could be a unique therapeutic strategy to treat GBM. We have previously identified TAZ as a master transcriptional activator of the MES phenotype. We found that TAZ is epigenetically silenced in IDH-MUT/PN gliomas. Silencing TAZ caused ablation of tumor growth implying that TAZ is an actionable target in gliomas.
Our preliminary investigations demonstrate that in addition to its transactivating functions, TAZ can cause active transcriptional repression of the PN signatures via enhancer reprogramming and silencing TAZ causes gain of PN cell fate. In this project, we will elucidate the molecular mechanisms by which TAZ blocks PN cell fate and examine the tumor suppressive effects of an inhibitor of TAZ and its PN repressor complex in combination with chemo-radiation in pre-clinical models of glioma.
Deciphering the immunosuppressive tumor microenvironment in GBM
With the advent of immunotherapy, the past few years has seen an explosion of studies describing the immune system and its critical role in cancer pathogenesis. However, the immune regulation of brain tumors is not fully established. Although for decades the brain has been considered as immune privileged, owing to an intact blood–brain barrier and the “absence” of lymphatic drainage system, recent discoveries prove the existence of a direct communication between the CNS and the immune system.
A variety of immune cell types including brain resident microglia, macrophages, T lymphocytes, natural killer cells and dendritic cells are found in the brain and play a role in immune surveillance. The activation of the immune system or its suppression in the GBM microenvironment depends on cell type/function and on the presence/absence of immune signals in the local environment.
The overall goals of this project is to characterize the immune landscape of GBMs using state of the art technologies and use this knowledge to elucidate how glioma cells promote alteration of tumor associated macrophages to an immune suppressive state.
Liquid biopsy approaches to GBM
A major challenge in the treatment of patients with GBM is the inability to provide longitudinal monitoring of the disease during therapy and during recurrence. Current methods of diagnoses include magnetic resonance imaging (MRI), as well as transcriptomic, genetic, and epigenomic profiling of nucleic acid extracted from biopsy of operable tissue, which only provide a static snapshot of the tumor. Furthermore, what appears to be initial success on post-operative MRI, as evidenced by >95% tumor resection, is soon followed by a challenge for radiologists in differentiating pseudo-progression caused by inflammation and edema (as a post-radiation side effect) from actual disease progression.
Adding to the complexity is the fact that both entities have similar contrast enhancement in MRI scans and both sets of patients present with similar clinical symptoms. Blood-based biomarkers for monitoring tumor progression such as circulating tumor cells and cell free DNA are attractive, but have yet to provide meaningful results in GBM (compared to other cancers) and have yet to become clinical diagnostics. Tumor educated platelets (TEPs) has recently been reported and shown to contain tumor-specific gene expression signatures that are associated with outcome for several tumor types, but the clinical value and the mechanisms of enrichment of TEPs are unknown. In this project, we will test the hypothesis that tumor-derived extracellular vesicles contain RNA cargo that is transferred to platelets and that these TEP RNA signatures derived from peripheral blood platelets can be utilized as biomarkers for longitudinal monitoring of disease progression.