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A CD133-AKT-Wnt signaling axis drives glioblastoma brain tumor-initiating cells

Oncogene volume 39, pages 1590–1599 (2020)Cite this article

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Abstract

Mechanistic insight into signaling pathways downstream of surface receptors has been revolutionized with integrated cancer genomics. This has fostered current treatment modalities, namely immunotherapy, to capitalize on targeting key oncogenic signaling nodes downstream of a limited number of surface markers. Unfortunately, rudimentary mechanistic understanding of most other cell surface proteins has reduced the clinical utility of these markers. CD133 has reproducibly been shown to correlate with disease progression, recurrence, and poor overall survivorship in the malignant adult brain tumor, glioblastoma (GBM). Using several patient-derived CD133high and CD133low GBMs we describe intrinsic differences in determinants of stemness, which we owe to a CD133-AKT-Wnt signaling axis in which CD133 functions as a putative cell surface receptor for AKT-dependent Wnt activation. These findings may have implications for personalized oncology trials targeting PI3K/AKT or Wnt as both pathways may be activated independent of their canonical drivers, leading to treatment resistance and disease relapse.

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Acknowledgements

B.M. is supported by a Canadian Institutes of Health Research Vanier Canada Graduate Scholarship. S.K.S. is supported by the Neurosurgical Research and Education Foundation and American Association of Neurological surgeons, Pediatric Section, the Ontario Institute for Cancer Research, and McMaster University Department of Surgery.

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Authors and Affiliations

  1. Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada

    Branavan Manoranjan

  2. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada

    Branavan Manoranjan, Chirayu Chokshi, Chitra Venugopal, Minomi Subapanditha, Neil Savage, Nazanin Tatari, Bradley W. Doble & Sheila K. Singh

  3. Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada

    Branavan Manoranjan, Chirayu Chokshi, Nazanin Tatari, Bradley W. Doble & Sheila K. Singh

  4. Departments of Pathology, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada

    John P. Provias

  5. Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada

    Naresh K. Murty & Sheila K. Singh

  6. The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada

    Jason Moffat

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Contributions

BM, CV, CC, BWD, SKS conceptualized and designed the experiments. BM, CV, CC, MS, NS, NT performed experiments and acquired data. BM, CV, CC, BWD, SKS analyzed and interpreted data. BM wrote the manuscript with revisions contributed by CV, CC, BWD, and SKS. JM provided non-commercial reagents. JPP, NKK provided GBM study samples. BWD and SKS supervised the study. All authors reviewed results and commented on the manuscript.

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Correspondence to Sheila K. Singh.

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Manoranjan, B., Chokshi, C., Venugopal, C. et al. A CD133-AKT-Wnt signaling axis drives glioblastoma brain tumor-initiating cells. Oncogene 39, 1590–1599 (2020). https://doi.org/10.1038/s41388-019-1086-x

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