The Kennedy Krieger Institute
Baltimore, Maryland, United States
The long term goal of my research is to understand the molecular mechanisms involved in regulating stemness and differentiation in neoplastic and non-neoplastic neural cells. We want to better understand Glioblastoma Multiforme (GBM) by studying the molecular mechanism by which these cells acquire a stem-like phenotype and use this knowledge to develop new ways to treat and diagnose the disease. Recent work in the Laterra lab has highlighted a reprogramming mechanism regulating reprogramming transcription factors resulting in dedifferentiation and maintenance of GBM stem-like cells. We recently uncovered a novel molecular circuit by which Oct4 and Sox2 co-expression induces glioma cell stemness and tumor propagating capacity by modifying miRNA networks that act to regulate the epigenetic landscape. We used complementary pharmacologic, genome screening and bisulfite sequencing approaches to show that Oct4/Sox2 induce DNMT-dependent DNA hyper-methylation that represses GBM SC inhibiting miRNAs with tumor-suppressing properties. We characterized two Oct4/Sox2 repressed miRNAs (i.e. miR-148a and miR-296-5p) that modify the epigenome by inhibiting DNMT and HMGA1 transcription. Reconstituting these miRNAs in GBM SCs was found to potently inhibit GBM cell stemness and most importantly the inhibition of tumor propagating capacity in vivo. We want to expand upon our current experimental model and conceptual paradigms and identify miRNAs and tumor suppressive pathways capable of inhibiting GBM stem-like tumor-propagating phenotype and apply that knowledge to develop new therapeutic approaches. As a young scientist, I would like to design and develop new approaches capable of bridging the gap between basic research and clinical application.
