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Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Author

Listed:
  • Erik Jung

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Matthias Osswald

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Miriam Ratliff

    (German Cancer Research Center (DKFZ)
    University Hospital Mannheim, University Heidelberg)

  • Helin Dogan

    (Ruprecht-Karls University Heidelberg
    German Cancer Research Center (DKFZ))

  • Ruifan Xie

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Sophie Weil

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Dirk C. Hoffmann

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Felix T. Kurz

    (University Hospital Heidelberg)

  • Tobias Kessler

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Sabine Heiland

    (University Hospital Heidelberg)

  • Andreas Deimling

    (Ruprecht-Karls University Heidelberg
    German Cancer Research Center (DKFZ))

  • Felix Sahm

    (Ruprecht-Karls University Heidelberg
    German Cancer Research Center (DKFZ))

  • Wolfgang Wick

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Frank Winkler

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

Abstract

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy—independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

Suggested Citation

  • Erik Jung & Matthias Osswald & Miriam Ratliff & Helin Dogan & Ruifan Xie & Sophie Weil & Dirk C. Hoffmann & Felix T. Kurz & Tobias Kessler & Sabine Heiland & Andreas Deimling & Felix Sahm & Wolfgang W, 2021. "Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21117-3
    DOI: 10.1038/s41467-021-21117-3
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    Cited by:

    1. Lata Adnani & Jordan Kassouf & Brian Meehan & Cristiana Spinelli & Nadim Tawil & Ichiro Nakano & Janusz Rak, 2022. "Angiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Cristiana Spinelli & Lata Adnani & Brian Meehan & Laura Montermini & Sidong Huang & Minjun Kim & Tamiko Nishimura & Sidney E. Croul & Ichiro Nakano & Yasser Riazalhosseini & Janusz Rak, 2024. "Mesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Marc Cicero Schubert & Stella Judith Soyka & Amr Tamimi & Emanuel Maus & Julian Schroers & Niklas Wißmann & Ekin Reyhan & Svenja Kristin Tetzlaff & Yvonne Yang & Robert Denninger & Robin Peretzke & Ca, 2024. "Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    4. Ling Hai & Dirk C. Hoffmann & Robin J. Wagener & Daniel D. Azorin & David Hausmann & Ruifan Xie & Magnus-Carsten Huppertz & Julien Hiblot & Philipp Sievers & Sophie Heuer & Jakob Ito & Gina Cebulla & , 2024. "A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1," Nature Communications, Nature, vol. 15(1), pages 1-29, December.
    5. Yun Chang & Xuechao Cai & Ramizah Syahirah & Yuxing Yao & Yang Xu & Gyuhyung Jin & Vijesh J. Bhute & Sandra Torregrosa-Allen & Bennett D. Elzey & You-Yeon Won & Qing Deng & Xiaojun Lance Lian & Xiaogu, 2023. "CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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