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 & 2 others Anja Voss-Böhme, Simone P. Niclou

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number1787
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Cite this

Dirkse, A., Golebiewska, A., Buder, T., Nazarov, P. V., Muller, A., Poovathingal, S., ... Niclou, S. P. (2019). Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nature Communications, 10(1), [1787]. https://doi.org/10.1038/s41467-019-09853-z
Dirkse, Anne ; Golebiewska, Anna ; Buder, Thomas ; Nazarov, Petr V. ; Muller, Arnaud ; Poovathingal, Suresh ; Brons, Nicolaas H. C. ; Leite, Sonia ; Sauvageot, Nicolas ; Sarkisjan, Dzjemma ; Seyfrid, Mathieu ; Fritah, Sabrina ; Stieber, Daniel ; Michelucci, Alessandro ; Hertel, Frank ; Herold-Mende, Christel ; Azuaje, Francisco ; Skupin, Alexander ; Bjerkvig, Rolf ; Deutsch, Andreas ; Voss-Böhme, Anja ; Niclou, Simone P. / Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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title = "Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment",
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.",
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Dirkse, A, Golebiewska, A, Buder, T, Nazarov, PV, Muller, A, Poovathingal, S, Brons, NHC, Leite, S, Sauvageot, N, Sarkisjan, D, Seyfrid, M, Fritah, S, Stieber, D, Michelucci, A, Hertel, F, Herold-Mende, C, Azuaje, F, Skupin, A, Bjerkvig, R, Deutsch, A, Voss-Böhme, A & Niclou, SP 2019, 'Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment' Nature Communications, vol. 10, no. 1, 1787. https://doi.org/10.1038/s41467-019-09853-z

Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. / Dirkse, Anne; Golebiewska, Anna; Buder, Thomas; Nazarov, Petr V.; Muller, Arnaud; Poovathingal, Suresh; Brons, Nicolaas H. C.; Leite, Sonia; Sauvageot, Nicolas; Sarkisjan, Dzjemma; Seyfrid, Mathieu; Fritah, Sabrina; Stieber, Daniel; Michelucci, Alessandro; Hertel, Frank; Herold-Mende, Christel; Azuaje, Francisco; Skupin, Alexander; Bjerkvig, Rolf; Deutsch, Andreas; Voss-Böhme, Anja; Niclou, Simone P.

In: Nature Communications, Vol. 10, No. 1, 1787, 01.12.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

AU - Dirkse, Anne

AU - Golebiewska, Anna

AU - Buder, Thomas

AU - Nazarov, Petr V.

AU - Muller, Arnaud

AU - Poovathingal, Suresh

AU - Brons, Nicolaas H. C.

AU - Leite, Sonia

AU - Sauvageot, Nicolas

AU - Sarkisjan, Dzjemma

AU - Seyfrid, Mathieu

AU - Fritah, Sabrina

AU - Stieber, Daniel

AU - Michelucci, Alessandro

AU - Hertel, Frank

AU - Herold-Mende, Christel

AU - Azuaje, Francisco

AU - Skupin, Alexander

AU - Bjerkvig, Rolf

AU - Deutsch, Andreas

AU - Voss-Böhme, Anja

AU - Niclou, Simone P.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-019-09853-z

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JO - Nature Communications

JF - Nature Communications

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