Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

Anne Dirkse, Anna Golebiewska (Main author), Thomas Buder, Petr V. Nazarov, Arnaud Muller, Suresh Poovathingal, Nicolaas H.C. Brons, Sonia Leite, Nicolas Sauvageot, Dzjemma Sarkisjan, Mathieu Seyfrid, Sabrina Fritah, Daniel Stieber, Alessandro Michelucci, Frank Hertel, Christel Herold-Mende, Francisco Azuaje, Alexander Skupin, Rolf Bjerkvig, Andreas DeutschAnja Voss-Böhme, Simone P. Niclou*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

289 Citations (Scopus)


The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.

Original languageEnglish
Article number1787
JournalNature Communications
Issue number1
Publication statusPublished - 1 Dec 2019


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