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

Anne Dirkse, Anna Golebiewska, 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 Deutsch, Anja Voss-Böhme and Simone P. Niclou ()
Additional contact information
Anne Dirkse: Luxembourg Institute of Health
Anna Golebiewska: Luxembourg Institute of Health
Thomas Buder: Technische Universität Dresden
Petr V. Nazarov: Luxembourg Institute of Health
Arnaud Muller: Luxembourg Institute of Health
Suresh Poovathingal: University of Luxembourg
Nicolaas H. C. Brons: Luxembourg Institute of Health
Sonia Leite: Luxembourg Institute of Health
Nicolas Sauvageot: Luxembourg Institute of Health
Dzjemma Sarkisjan: Luxembourg Institute of Health
Mathieu Seyfrid: Luxembourg Institute of Health
Sabrina Fritah: Luxembourg Institute of Health
Daniel Stieber: Luxembourg Institute of Health
Alessandro Michelucci: Luxembourg Institute of Health
Frank Hertel: Centre Hospitalier Luxembourg
Christel Herold-Mende: University of Heidelberg
Francisco Azuaje: Luxembourg Institute of Health
Alexander Skupin: University of Luxembourg
Rolf Bjerkvig: Luxembourg Institute of Health
Andreas Deutsch: Technische Universität Dresden
Anja Voss-Böhme: Technische Universität Dresden
Simone P. Niclou: Luxembourg Institute of Health

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09853-z

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