Characterizing the role of Tenascin-C (TNC) in pediatric glioma as a marker of tumorigenesis and novel therapeutic target
We previously identified increased Tenascin-C (TNC) protein expression in tumor tissue and cerebrospinal fluid (CSF) in DIPG patients, with highest TNC expression levels observed in K27M mutants. TNC is an extracellular matrix protein that modulates the mitogenic effects of PDGF and NOTCH signaling in oligodendroglial precursor cells (OPCs), the purported cells of origin for DIPG. In adult glioma, TNC expression is associated with NOTCH activation, which is a component of the Hh pathway. TNC overexpression in adult glioma correlates with tumor recurrence, local invasion and poor overall survival. However, the role of TNC expression in pediatric gliomas, and its potential as a therapeutic target, has yet to be explored.
Through a series of in vivo and in vitro studies, we aim to characterize the nature, frequency and variation in level of TNC overexpression in pediatric HGG and DIPG cell lines, tumor tissue, serum and CSF. The molecular and effects of modulating TNC expression on tumor cell biology and function are investigated in vitro and in vivo in order to determine the mechanism of TNC overexpression in pediatric glioma and its role as a novel therapeutic target.
Exploring the Histone H3K27M mutation as a driver of pediatric gliomagenesis
Epigenetic regulation of gene expression has been implicated in a variety of human diseases, including cancer. Recently, point mutations in histone H3 have been identified in up to 80% of pediatric midline gliomas, causing altered chromatin function and extensive transcriptome reprogramming. Our group is working to elucidate the mechanism by which histone H3 post-translational modifications in H3K27M mutant glioma alter gene transcription to contribute to tumor formation and progression. Integrating RNA-Seq, ChIP-Seq and proteomic analysis of rare patient-derived tumor specimens and primary glioma cell lines, we are working to identify epigenetic “signatures” of disease and characterize alterations in gene expression in DIPG associated with specific histone H3 transcriptional regulatory marks. In turn, we are evaluating the enzymatic mechanisms responsible for these histone modifications to determine if these represent rational therapeutic targets. Importantly, our group recently demonstrated that H3 mutations are detectable in the cerebrospinal fluid (CSF) from patients with midline and supratentorial hemispheric glioma. We are therefore working to expand this “liquid biopsy” approach for mutation detection for clinical tumor diagnosis, stratification to targeted therapy and monitoring treatment response.