Differentiated glioma cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth

  1. Shreoshi Sengupta
  2. Mainak Mondal
  3. Kaval Reddy Prasasvi
  4. Arani Mukherjee
  5. Prerna Magod
  6. Serge Urbach
  7. Dinorah Friedmann-Morvinski  Is a corresponding author
  8. Philippe Marin  Is a corresponding author
  9. Kumaravel Somasundaram  Is a corresponding author
  1. Indian Institute of Science Bangalore, India
  2. Tel Aviv University, Israel
  3. Institut de Génomique Fonctionnelle, CNRS, INSERM, France

Abstract

Cancer stem cells (CSCs) alone can initiate and maintain tumors, but the function of non-cancer stem cells (non-CSCs) that form the tumor bulk remains poorly understood. Proteomic analysis showed a higher abundance of the extracellular matrix small leucine-rich proteoglycan Fibromodulin (FMOD) in the conditioned medium of differentiated glioma cells (DGCs), the equivalent of glioma non-CSCs, compared to that of glioma stem-like cells (GSCs). DGCs silenced for FMOD fail to cooperate with co-implanted GSCs to promote tumor growth. FMOD downregulation neither affects GSC growth and differentiation nor DGC growth and reprogramming in vitro. DGC-secreted FMOD promotes angiogenesis by activating Integrin-dependent Notch signaling in endothelial cells. Furthermore, conditional silencing of FMOD in newly generated DGCs in vivo inhibits the growth of GSC-initiated tumors due to poorly developed vasculature and increases mouse survival. Collectively, these findings demonstrate that DGC-secreted FMOD promotes glioma tumor angiogenesis and growth through paracrine signaling in endothelial cells and identifies a DGC-produced protein as a potential therapeutic target in glioma.

Data availability

Label-free mass spectrometry data between the GSC and DGC showing protein ratios in the GSC and DGC secretome and p values are shown in Supplementary File 1 for proteins exhibiting significant differences in abundance in both conditions. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD032958.

Article and author information

Author details

  1. Shreoshi Sengupta

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Mainak Mondal

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Kaval Reddy Prasasvi

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Arani Mukherjee

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Prerna Magod

    School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Serge Urbach

    Institut de Génomique Fonctionnelle, CNRS, INSERM, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Dinorah Friedmann-Morvinski

    School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel
    For correspondence
    dino@tauex.tau.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6394-9876
  8. Philippe Marin

    Institut de Génomique Fonctionnelle, CNRS, INSERM, Montpellier, France
    For correspondence
    philippe.marin@igf.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5977-7274
  9. Kumaravel Somasundaram

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    For correspondence
    skumar1@iisc.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6228-9741

Funding

Department of Biotechnology, Ministry of Science and Technology, India

  • Kumaravel Somasundaram

Department of Science and Technology, Ministry of Science and Technology, India

  • Kumaravel Somasundaram

Indo-French Centre for the Promotion of Advanced Research (n{degree sign} IFC/5603-C/2016/503)

  • Kumaravel Somasundaram

Israel Science Foundation (Grant no.1315/15 and 1429/20)

  • Dinorah Friedmann-Morvinski

Fondation pour la Recherche Médicale

  • Philippe Marin

Indo-French Centre for the Promotion of Advanced Research (n{degree sign} IFC/5603-C/2016/503)

  • Philippe Marin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The Institute Ethical Committee for Animal Experimentation (Institute Animal Ethics Committee [IAEC] Project Number: CAF/Ethics/752/2020)

Reviewing Editor

  1. Caigang Liu, Shengjing Hospital of China Medical University, China

Publication history

  1. Received: March 25, 2022
  2. Accepted: May 29, 2022
  3. Accepted Manuscript published: June 1, 2022 (version 1)
  4. Accepted Manuscript updated: June 6, 2022 (version 2)

Copyright

© 2022, Sengupta et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shreoshi Sengupta
  2. Mainak Mondal
  3. Kaval Reddy Prasasvi
  4. Arani Mukherjee
  5. Prerna Magod
  6. Serge Urbach
  7. Dinorah Friedmann-Morvinski
  8. Philippe Marin
  9. Kumaravel Somasundaram
(2022)
Differentiated glioma cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth
eLife 11:e78972.
https://doi.org/10.7554/eLife.78972

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