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Glioblastoma stem cells exploit the αvβ8 integrin-TGFβ1 signaling axis to drive tumor initiation and progression

Oncogene volume 36, pages 6568–6580 (2017)Cite this article

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Abstract

Glioblastoma (GBM) is a primary brain cancer that contains populations of stem-like cancer cells (GSCs) that home to specialized perivascular niches. GSC interactions with their niche influence self-renewal, differentiation and drug resistance, although the pathways underlying these events remain largely unknown. Here, we report that the integrin αvβ8 and its latent transforming growth factor β1 (TGFβ1) protein ligand have central roles in promoting niche co-option and GBM initiation. αvβ8 integrin is highly expressed in GSCs and is essential for self-renewal and lineage commitment in vitro. Fractionation of β8high cells from freshly resected human GBM samples also reveals a requirement for this integrin in tumorigenesis in vivo. Whole-transcriptome sequencing reveals that αvβ8 integrin regulates tumor development, in part, by driving TGFβ1-induced DNA replication and mitotic checkpoint progression. Collectively, these data identify the αvβ8 integrin-TGFβ1 signaling axis as crucial for exploitation of the perivascular niche and identify potential therapeutic targets for inhibiting tumor growth and progression in patients with GBM.

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Acknowledgements

We would like to thank colleagues in the M.D. Anderson Neurosurgery department for providing freshly resected human samples. This work was supported by grants to JHM from NIH/NINDS (R01NS0 7635 and R01NS078402), the Cancer Prevention and Research Institute of Texas (RP140411), and in part by an NIH/NCI SPORE in Brain Cancer (P50CA127001).

Author contributions

PAG, JHT, ZC, JEM, QG, EPS and NM performed critical experiments. FFL, GR and GF contributed important experimental reagents. PAG and JHM wrote the manuscript.

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Authors and Affiliations

  1. Department of Neurosurgery, M. D. Anderson Cancer Center, Houston, TX, USA,

    P A Guerrero, J H Tchaicha, Z Chen, J E Morales, F F Lang, G Rao & J H McCarty

  2. The Brown Institute for Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA,

    N McCarty

  3. Department of Radiation Oncology, M. D. Anderson Cancer Center, Houston, TX, USA,

    Q Wang & E P Sulman

  4. Department of Genomic Medicine, M. D. Anderson Cancer Center, Houston, TX, USA,

    Q Wang & E P Sulman

  5. Department of Translational Molecular Pathology, M. D. Anderson Cancer Center, Houston, TX, USA,

    E P Sulman

  6. Departments of Pathology, M. D. Anderson Cancer Center, Houston, TX, USA,

    G Fuller

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  1. P A Guerrero
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  2. J H Tchaicha
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Correspondence to J H McCarty.

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Guerrero, P., Tchaicha, J., Chen, Z. et al. Glioblastoma stem cells exploit the αvβ8 integrin-TGFβ1 signaling axis to drive tumor initiation and progression. Oncogene 36, 6568–6580 (2017). https://doi.org/10.1038/onc.2017.248

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