Non-cancer stem cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth

Somasundaram, K.; Sengupta, S.; Mondal, M.; Prasasvi, K. R.; Mukherjee, A.; Magod, P.; Urbach, S.; Friedmann-Morvinski, D.; Marin, P.

doi:10.1101/2022.04.03.486893

bioRxiv · 10.1101/2022.04.03.486893

Non-cancer stem cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth

Somasundaram, K.·Sengupta, S.·Mondal, M.·Prasasvi, K. R.·Mukherjee, A.·Magod, P.·Urbach, S.·Friedmann-Morvinski, D.·Marin, P.

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Abstract

Cancer stem cells alone can initiate and maintain tumors, but the function of non-cancer stem cells 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 non-cancer stem cells (DGCs; differentiated glioma cells) of glioma 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.

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Somasundaram, K., Sengupta, S., Mondal, M., Prasasvi, K. R., Mukherjee, A., Magod, P., Urbach, S., Friedmann-Morvinski, D., Marin, P.. 2022-04-06. Non-cancer stem cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth. https://doi.org/10.1101/2022.04.03.486893

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