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Brain cancer stem cells: resilience through adaptive plasticity and hierarchical heterogeneity

Nature Reviews Cancer volume 22, pages 497–514 (2022)Cite this article

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Abstract

Malignant brain tumours are complex ecosystems containing neoplastic and stromal components that generate adaptive and evolutionarily driven aberrant tissues in the central nervous system. Brain cancers are cultivated by a dynamic population of stem-like cells that enforce intratumoural heterogeneity and respond to intrinsic microenvironment or therapeutically guided insults through proliferation, plasticity and restructuring of neoplastic and stromal components. Far from a rigid hierarchy, heterogeneous neoplastic populations transition between cellular states with differential self-renewal capacities, endowing them with powerful resilience. Here we review the biological machinery used by brain tumour stem cells to commandeer tissues in the intracranial space, evade immune responses and resist chemoradiotherapy. Through recent advances in single-cell sequencing, improved models to investigate the role of the tumour microenvironment and a deeper understanding of the fundamental role of the immune system in cancer biology, we are now better equipped to explore mechanisms by which these processes can be exploited for therapeutic benefit.

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Fig. 1: Conceptual framework and molecular circuitry of glioblastoma stem cells.
Fig. 2: Glioblastoma stem cell hierarchical plasticity, developmental origin, classification methods and evolution.
Fig. 3: Brain cancer stem cells in context: tumour microenvironmental inputs.

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Acknowledgements

The authors apologize to the authors of the many outstanding publications not referenced here owing to space restrictions. R.C.G is supported by US National Institutes of Health (NIH) grant F30CA217065. K.Y. is supported by the Computational Genomic Epidemiology of Cancer program at Case Comprehensive Cancer Center (T32CA094186), the Young Investigator Award in Glioblastoma from Conquer Cancer, the ASCO Foundation, and an RSNA research resident grant. M.E.H. is funded by the Joshua’s Wish Foundation. S.A. is funded by NIH grant R01NS115831, the Michael Mosier Defeat DIPG Foundation and the V Foundation (Connor’s Cure). J.N.R. is supported by NIH grants R35CA197718, R01CA238662 and R01NS103434.

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Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    Ryan C. Gimple

  2. Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA

    Kailin Yang

  3. Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Matthew E. Halbert & Sameer Agnihotri

  4. University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA

    Jeremy N. Rich

  5. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    Jeremy N. Rich

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  1. Ryan C. Gimple
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  5. Jeremy N. Rich
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The authors contributed equally to all aspects of the article.

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Glossary

Lineage infidelity

Process by which cells differentiated along a particular developmental lineage lose their original identity and assume a more primitive developmental state or display features of a distinct differentiated lineage.

Single-cell sequencing

An array of methods to assess genomic, epigenomic or transcriptomic states of individual cells through next-generation sequencing approaches. These techniques allow resolution of distinct cellular populations, identification of new cell types or states, acquisition of information on expression dynamics and insights into cellular and tissue evolution, among other characteristics.

DNA barcoding

Method of individually labelling single cells or a cellular population for tracking over time, with applications in cell tracing and reconstruction of evolutionary lineages. Cell labelling can be accomplished with lentiviral or CRISPR-based transduction approaches and interrogated with flow cytometry, sequencing or imaging, and analysis can be performed with single-cell resolution.

Subventricular zone

Anatomic region in the brain situated along the lateral ventricles that contains populations of proliferative immature neural lineages. This region gives rise to more differentiated progeny through the process of neurogenesis, with possible links to gliomagenesis.

Organoid

Three-dimensional, self-organizing heterogeneous cellular collections derived from stem-like populations and consisting of a variety of cell states used to model cellular interactions and higher-order functions of tissue systems, including tissue regeneration, maintenance and cellular connectivity in both neoplastic and non-neoplastic settings.

Mitotic somal translocation

Characteristic migratory behaviour of outer radial glial cells in which the cell body rapidly moves from the outer subventricular zone towards the cortical plate immediately before cell division during neurogenesis.

Oncohistone mutations

Mutations in a variety of histone proteins that promote cancer growth primarily through disruptions in the global histone post-translational modification landscape and disrupted epigenetic regulation. In brain tumours, common mutations include K27M (histone H3) in diffuse intrinsic pontine gliomas and G34V/R (histone H3) in paediatric glioblastomas, among others.

RNA velocity analysis

Method to estimate the rate of change of transcriptional states of cells in single-cell sequencing studies through comparison of the ratio of newly transcribed (unspliced) transcripts to mature transcripts (spliced) and to infer expression dynamics and future cellular states.

Temozolomide

Alkylating chemotherapy agent with blood–brain barrier penetrance that serves as standard-of-care treatment for patients with glioblastoma alongside surgical resection and radiotherapy.

Branched and neutral evolution

Different models to describe the emergence of intratumoural genetic heterogeneity and development of lineage trajectories in cancers. Branched evolution models suggest that heterogeneous clones emerge on the basis of a selective advantage and evolve in parallel, while neutral evolution models posit that intratumoural heterogeneity is driven primarily by random mutations and genetic drift without strong selective forces. Branched and neutral evolution models describe relatively high intratumoural heterogeneity, while linear or punctuated evolution models consist of lower heterogeneity at a given time point driven by single clones with increased fitness.

Extrachromosomal circular DNA

Collections of circular DNA sequences lacking centromeres that exist outside chromosomes and which can be replicated and differentially segregated to daughter cells during cell division, with important implications for intratumoural heterogeneity and cancer evolution. Extrachromosomal circular DNA can lead to massive amplification of oncogenes and products facilitating therapy resistance, can consist of highly rearranged genomic sequences and is thought to arise through the process of genomic shattering (chromothripsis) with disrupted DNA damage repair pathways, although competing models exist.

Microvascular proliferation

Characteristic histologic hallmark of glioblastomas referring to pathogenic glomeruloid proliferation of mitotically active and multilayered hyperplastic endothelial cells secondary to high angiogenic activity of VEGF that may be associated with areas of hypoxia and necrosis.

Circadian rhythm

Cell-intrinsic or multisystem process that occurs on a 24-h cycle and is maintained through cyclical production and degradation of circadian protein complexes or entrained through endocrine signalling mechanisms. While circadian rhythms on the whole-organism level can be controlled through exposure to light cycles, independent molecular clocks exist within many individual single cell types driven by peripheral oscillator transcriptional networks, including CLOCK, BMAL1, PER and CRY.

Chimeric antigen receptor (CAR) T cells

Synthetic T lymphocytes containing an engineered T cell receptor targeted against a specific antigen with optimized intracellular signalling components to coordinate antitumour immune responses and facilitate cancer cell killing in experimental and clinically validated immunotherapies. CAR T cells can be expanded in vitro and then infused into patients, serving as a ‘living drug’ with capacity to expand in vivo and generate memory responses.

Synthetic Notch receptor

Customized receptor generated through cellular engineering approaches to sense particular extracellular signals and coordinate a specific programmable intracellular response via a regulatory transmembrane domain and an effector intracellular domain such as a transcription factor. This highly tuneable tool enables sensing of specific signals to be coupled with a downstream effector response via a synthetic biology approach, with applications in cancer immunotherapy and beyond.

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Gimple, R.C., Yang, K., Halbert, M.E. et al. Brain cancer stem cells: resilience through adaptive plasticity and hierarchical heterogeneity. Nat Rev Cancer 22, 497–514 (2022). https://doi.org/10.1038/s41568-022-00486-x

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