Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Uhm, Joon H.

doi:10.1016/s0513-5117(09)79089-1

Cited by 3 publications

(1 citation statement)

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“…Temozolomide (TMZ) chemotherapy represents the last major widespread applied advance in GBM therapy (Stupp et al, 2005), although its efficacy is remarkably limited, and it endows tumors with an additional mutational burden that may ultimately drive disease progression (Cancer Genome Atlas Research Network, 2008;Hunter et al, 2006). While large-scale genomic analyses of human GBM tumor samples has revealed a complex genomic architecture (Brennan et al, 2013;Parsons et al, 2008;Uhm, 2009), this has been difficult to link to GBM growth and functional cell properties, particularly due to the tumors' proliferative and cellular heterogeneity. Indeed, a more comprehensive understanding of molecular determinants of growth and drug responsiveness across this heterogenous cancer is needed, both to identify new therapeutic opportunities and to also provide new strategies that could be partnered with TMZ that is now entrenched in upfront GBM therapy.…”

Section: Introductionmentioning

confidence: 99%

The functional genomic circuitry of human glioblastoma stem cells

MacLeod

Bozek

Rajakulendran

et al. 2018

Preprint

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SummarySuccessful glioblastoma (GBM) therapies have remained elusive due to limitations in understanding mechanisms of growth and survival of the tumorigenic population. Using CRISPR-Cas9 approaches in patient-derived GBM stem cells to interrogate function of the coding genome, we identify diverse actionable pathways responsible for growth that reveal the gene-essential circuitry of GBM stemness. In particular, we describe the Sox developmental transcription factor family; H3K79 methylation by DOT1L; and ufmylation stress responsiveness programs as essential for GBM stemness. Additionally, we find mechanisms of temozolomide resistance and sensitivity that could lead to combination strategies with this standard of care treatment. By reaching beyond static genome analysis of bulk tumors, with a genome wide functional approach, we dive deep into a broad range of biological processes to provide new understanding of GBM growth and treatment resistance.SignificanceGlioblastoma (GBM) remains an incurable disease despite an increasingly thorough depth of knowledge of the genomic and epigenomic alterations of bulk tumors. Evidence from multiple approaches support that GBM reflects an aberrant developmental hierarchy, with GBM stem cells (GSCs), fueling tumor growth and invasion. The properties of this tumor subpopulation may also in part explain treatment resistance and disease recurrence. Unfortunately, we still have a limited knowledge of the molecular circuitry of these cells and progress has been slow as we have not been able, until recently, to interrogate function at the genome-wide scale. Here, using parallel genome-wide CRISPR-Cas9 screens, we identify the essential genes for GSC growth. Further, by screening in the presence of low and high dose temozolomide, we identify mechanisms of drug resistance and sensitivity. These functional screens in patient derived cells reveal new aspects of GBM biology and identify a diversity of actionable targets such as genes governing stem cell traits, epigenome regulation and the response to stress stimuli.

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