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30.08.17 Barcoding brain cancer cells helps to simplify understanding of tumour growth and treatment strategy

last modified Aug 30, 2017 06:38 PM
In this Nature article, the Simons lab and collaborators track the patterns of glioblastoma cell division and differentiation

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy

Lan X et al. (2017) Nature DOI: 10.1038/nature23666  [Advance online publication] 

 

Author's summary: Tracing the fate of tumour cells in brain cancer

In cancer biology, much emphasis is placed on deciphering the sequence of mutational events that drive tumour development. Yet, by focusing on the mutational signature, the manner in which these mutations act to subvert the fate behaviour of tumour cells is often overlooked, limiting the scope to discover new therapeutic strategies.

Attempts to trace the dynamics of individual tumour cells and their progeny using transgenic animal models have highlighted the role played by minority cell subpopulations in sustaining tumour growth – a controversial concept known as the “cancer stem cell” hypothesis. However, the extent to which the activation of targeted oncogenic -cancer-initiating- mutations in animal models recapitulates the natural process of tumour development in human is also questionable. 

In a multidisciplinary study, Benjamin Simons and David Jörg at the Wellcome Trust/Cancer Research UK Gurdon Institute have teamed up with Peter Dirks, a consultant physician and researcher at the Hospital for Sick Children at the University of Toronto, to study cell fate behaviour in human glioblastoma, a type of brain cancer that affects around 1,000 adults and 100 children in the UK every year, and is notorious for poor response to treatment. Their approach is based on a novel tagging method where primary cancer cells are marked with a unique genetic “barcode” prior to transplantation into mice. By measuring the contributions made by individual cells to tumour growth, they have been able to decode the “rules” of cell fate. It is like trying to infer the rules of a card game by simply watching how rounds of hands unfold.

Surprisingly, despite the cells' mutational heterogeneity, this study showed that tumour cells conform to a remarkably conserved cellular hierarchy, with features reminiscent of a “normal” developmental programme. The researchers could also detect rare outlier cell lineages – known as “clones” – that have a different, more aggressive, growth characteristic that becomes selected for during drug therapy. Based on these findings, the researchers went on to find drug combinations that could selectively target these two types of clones.

As well as emphasising the importance of stem cell-like hierarchies in human brain tumour growth, these findings demonstrate that intra-tumoural heterogeneity, a hallmark of many common cancers, may not correlate with variability in the mutational landscape, but may instead emerge as the outcome of chance fate decisions made within a surprisingly homogeneous tumour cell population.

By focusing on the functional fate behaviour of tumour cells, rather than their mutational signature, this study reveals that the aberrant reactivation of developmental programmes may play a key role in driving cancer growth, exposing new therapeutic strategies that target cell differentiation rather than proliferation.

 

Abstract from the paper

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells.

In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare ‘outlier’ clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.

 

Read more about research in the Simons lab.

Watch Ben Simons describe why he uses physics to understand cell behaviour.

 

 

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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