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Tenascin C promotes cancer cell plasticity in mesenchymal glioblastoma

Abstract

Interconversion of transformed non-stem cells to cancer stem cells, termed cancer cell plasticity, contributes to intra-tumor heterogeneity and its molecular mechanisms are currently unknown. Here, we have identified Tenascin C (TNC) to be upregulated and secreted in mesenchymal glioblastoma (MES GBM) subtype with high NF-κB signaling activity. Silencing TNC decreases proliferation, migration and suppresses self-renewal of glioma stem cells. Loss of TNC in MES GBM compromises de-differentiation of transformed astrocytes and blocks the ability of glioma stem cells to differentiate into tumor derived endothelial cells (TDEC). Inhibition of NF-κB activity or TNC knockdown in tumor cells decreased their tumorigenic potential in vivo. Our results uncover a link between NF-κB activation in MES GBM and high levels of TNC in GBM extracellular matrix. We suggest that TNC plays an important role in the autocrine regulation of glioma cell plasticity and hence can be a potential molecular target for MES GBM.

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Fig. 1: TNC is overexpressed in lentiviral-induced MES GBM mouse model.
Fig. 2: Silencing TNC reduces glioma cell proliferation and invasion, induces apoptosis and affects stem cell maintenance in vitro.
Fig. 3: Depletion of TNC compromises glioma cell plasticity.
Fig. 4: Silencing TNC impairs endothelial differentiation of glioma stem cells.
Fig. 5: Blocking NF-κB signaling reduces TNC expression and impairs glioma cell plasticity.
Fig. 6: Silencing TNC suppresses murine 005 tumor growth and reduces blood vessel formation.
Fig. 7: Specific inhibition of TNC in human GBM-bearing mice improves survival.

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Acknowledgements

We thank Yifeng Xia and Eugene Ke for assistance in bioinformatic analysis, and Prof. Michal Baniyash for critically reading the manuscript. This research was supported by grants to DF-M from the Israel Science Foundation (Grant no. 1310/15), the Israel Cancer Research Fund (Research Career Development Award), and the EU-FP7 Marie Curie Actions (Career Integration Grant).

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DF-M designed the research, IA, OPK, LRN and DFM performed the experiments, IA and DFM analyzed the results, IA and DFM wrote the manuscript

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Correspondence to Dinorah Friedmann-Morvinski.

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Angel, I., Pilo Kerman, O., Rousso-Noori, L. et al. Tenascin C promotes cancer cell plasticity in mesenchymal glioblastoma. Oncogene 39, 6990–7004 (2020). https://doi.org/10.1038/s41388-020-01506-6

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