5 years ago

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy
Martin Hirst, Lilian Lee, Xiaoyang Lan, Andrew J. Mungall, Davide Pellacani, Annaick Carles, Laura M. Richards, Mathieu Lupien, Hayden J. Selvadurai, Richard A. Moore, Fiona J. Coutinho, Peter B. Dirks, Cheryl H. Arrowsmith, Michael D. Taylor, Paul Guilhamon, Nicole I. Park, Michelle Moksa, Michelle M. Kushida, Sonam Dolma, Long V. Nguyen, Marco Gallo, Yussanne Ma, Clare Che, Heather Whetstone, Connie J. Eaves, Naghmeh Rastegar, Michael D. Cusimano, Florence M. G. Cavalli, David J. Jörg, Betty Luu, Robert J. Vanner, Benjamin D. Simons, Trevor J. Pugh, Mark Bernstein, Sunit Das, Renee Head, Panagiotis Prinos
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.

Publisher URL: http://dx.doi.org/10.1038/nature23666

DOI: 10.1038/nature23666

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.