Glioma stem cells (GSCs) from human glioblastoma (GBM) are resistant to radiation and chemotherapy and may drive disease recurrence after therapy. Understanding the genesis of GSCs will be critical to the design of novel therapeutic approaches to manage GBM.

Project summary

We investigate the molecular mechanisms of GSC development using genetically-engineered mouse (GEM) models and human patient-derived xenografts (PDX).

In particular, we focus on the molecular mechanisms by which astrocytes, the most abundant glial cell type in the mammalian brain, de-differentiate into GSC after acquiring oncogenic mutations in core glioblastoma signaling pathways.

Brennan et al.  Cancer Cell 155(2):462 2013.

Mechanistic studies use GEM and PDX culture systems to:

Examine how core pathway mutations induce GSC-specific alterations in the epigenetic landscape of astrocytes

Integrated genomics analyses are critical for this work.  These include FAIRE– and ATAC-seq, ChIP-seq, and RNA-seq to examine mutation-induced changes in chromatin accessibility, promoter landscapes, and transcriptomes.

Schmid et al.  Neuro-oncology 18(7):962 2016.

Define the transcription factors that mediate oncogenic mutation-induced astrocyte de-differentiation into GSC

Cell culture techniques used in developmental neurobiology are critical for this work.  These include analysis of self-renewal using neurosphere culture, extreme-limiting dilution, and multi-lineage differentiation assays.

Schmid et al.  Neuro-oncology 18(7):962 2016.

References

  1. Schmid RS, Simon JM, Vitucci M, McNeill RS, Bash RE, Werneke AM, Huey L, White KK, Ewend MG, Wu J, Miller CR.  Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation, but resistant to temozolomide.  Neuro-oncology.  18(7):962-973 Jul 2016.  PMID: 26826202  PMCID: PMC4896545
  2. McNeill RS, Vitucci M, Wu J, Miller CR.  Contemporary murine models in preclinical astrocytoma drug development.  Neuro-oncology.  17(1):12-28 Jan 2015.  PMID: 25246428  PMCID: PMC4483055
  3. McNeill RS, Schmid RS, Bash RE, Vitucci M, White KK, Werneke AM, Constance BH, Huff B, Miller CR.  Modeling astrocytoma pathogenesis in vitro and in vivo using cortical astrocytes or neural stem cells from conditional, genetically engineered mice.  Journal of Visualized Experiments.  90:e51763 Aug 2014.  PMID: 25146643
  4. Vitucci M, Karpinich NO, Bash RE, Werneke AM, Schmid RS, White KK, McNeill RS, Huff B, Wang S, Van Dyke T, Miller CR.  Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis.  Neuro-oncology.  15(10):1317-1329 Oct 2013.  PMID: 23814263  PMCID: PMC3779038