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

Author

Listed:
  • Anne Dirkse

    (Luxembourg Institute of Health
    University of Luxembourg)

  • Anna Golebiewska

    (Luxembourg Institute of Health)

  • Thomas Buder

    (Technische Universität Dresden
    Fakultät Informatik/Mathematik, Hochschule für Technik und Wirtschaft 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
    University of Luxembourg)

  • 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
    University of Bergen)

  • Andreas Deutsch

    (Technische Universität Dresden)

  • Anja Voss-Böhme

    (Technische Universität Dresden
    Fakultät Informatik/Mathematik, Hochschule für Technik und Wirtschaft Dresden)

  • Simone P. Niclou

    (Luxembourg Institute of Health)

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.

Suggested Citation

  • 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 & S, 2019. "Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09853-z
    DOI: 10.1038/s41467-019-09853-z
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    Cited by:

    1. Cathy Pichol-Thievend & Oceane Anezo & Aafrin M. Pettiwala & Guillaume Bourmeau & Remi Montagne & Anne-Marie Lyne & Pierre-Olivier Guichet & Pauline Deshors & Alberto Ballestín & Benjamin Blanchard & , 2024. "VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    2. Yael Aylon & Noa Furth & Giuseppe Mallel & Gilgi Friedlander & Nishanth Belugali Nataraj & Meng Dong & Ori Hassin & Rawan Zoabi & Benjamin Cohen & Vanessa Drendel & Tomer Meir Salame & Saptaparna Mukh, 2022. "Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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