Abstract
ABSTRACTGlioblastoma multiforme (GBM) is one of the deadliest human cancers. Despite increasing knowledge of the genetic and epigenetic changes that underlie tumour initiation and growth, the prognosis for GBM patients remains dismal. Genome analysis has failed to lead to success in the clinic. Fresh approaches are needed that can stimulate new discoveries across all levels: cell-intrinsic mechanisms (transcriptional/epigenetic and metabolic), cell-cell signalling, niche and microenvironment, systemic signals, immune regulation, and tissue-level physical forces. GBMs are inherently extremely challenging: tumour detection occurs too late, and cells infiltrate widely, hiding in quiescent states behind the blood-brain barrier. The complexity of the brain tissue also provides varied and complex microenvironments that direct cancer cell fates. Phenotypic heterogeneity is therefore superimposed onto pervasive genetic heterogeneity. Despite this bleak outlook, there are reasons for optimism. A myriad of complementary, and increasingly sophisticated, experimental approaches can now be used across the research pipeline, from simple reductionist models devised to delineate molecular and cellular mechanisms, to complex animal models required for preclinical testing of new therapeutic approaches. No single model can cover the breadth of unresolved questions. This Review therefore aims to guide investigators in choosing the right model for their question. We also discuss the recent convergence of two key technologies: human stem cell and cancer stem cell culture, as well as CRISPR/Cas tools for precise genome manipulations. New functional genetic approaches in tailored models will likely fuel new discoveries, new target identification and new therapeutic strategies to tackle GBM.
Highlights
Cellular and genetic heterogeneityImmune cells in the surrounding microenvironment paradigms and high-content phenotypic screening are stimulating new approaches to functional genetic dissection and drug discovery efforts (O’Duibhir and Pollard, 2017)
The challenges of glioblastoma multiforme Glioblastoma multiforme (GBM) is the most common malignant primary brain tumour
Because GBMs often arise in young adults and have poor prognosis, they account for more years of MRC Centre for Regenerative Medicine and Edinburgh Cancer Research UK Cancer Centre, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
Summary
Immune cells in the surrounding microenvironment paradigms and high-content phenotypic screening are stimulating new approaches to functional genetic dissection and drug discovery efforts (O’Duibhir and Pollard, 2017). Patient-derived primary GBM cells cultured under similar conditions can be sustained long term, either in suspension or adherent (on laminin) culture (Galli et al, 2004; Hemmati et al, 2003; Pollard et al, 2009; Singh et al, 2003) These retain the genetics and transcriptional state of the parental tumour, unlike the serum-grown ‘classic’ cell lines (Lee et al, 2006). Organoid culture paradigms enable the ex vivo growth of primary GBM specimens to a large size (Hubert et al, 2016) This allows modelling of the necrotic and hypoxic features of human tumours, alongside the corresponding greater range of quiescent, proliferative and differentiating cell states (Hubert et al, 2016). Cells isolated from these organoid tumours bear the molecular signature of REVIEW Rodent model Adult patient
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