Differentiated glioma cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth
- Indian Institute of Science Bangalore, India
- Tel Aviv University, Israel
- Institut de Génomique Fonctionnelle, Université de Montpellier, 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
Dinorah Friedmann-Morvinski
Kumaravel Somasundaram
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.
Reviewing Editor
- Caigang Liu, Shengjing Hospital of China Medical University, China
Ethics
Animal experimentation: The Institute Ethical Committee for Animal Experimentation (Institute Animal Ethics Committee [IAEC] Project Number: CAF/Ethics/752/2020)
Version history
- Received: March 25, 2022
- Preprint posted: April 6, 2022 (view preprint)
- Accepted: May 29, 2022
- Accepted Manuscript published: June 1, 2022 (version 1)
- Accepted Manuscript updated: June 6, 2022 (version 2)
- Version of Record published: July 6, 2022 (version 3)
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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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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