Abstract

Despite advances in therapy, glioblastoma remains an incurable disease with a dismal prognosis. Recent studies have implicated cancer stem cells within glioblastoma (glioma stem cells, GSCs) as mediators of therapeutic resistance and tumor progression. In this study, we investigated the role of the transforming growth factor-β (TGF-β) superfamily, which has been found to play an integral role in the maintenance of stem cell homeostasis within multiple stem cell systems, as a mediator of stem-like cells in glioblastoma. We find that BMP and TGF-β signaling define divergent molecular and functional identities in glioblastoma, and mark relatively quiescent and proliferative GSCs, respectively. Treatment of GSCs with BMP inhibits cell proliferation, but does not abrogate their stem-ness, as measured by self-renewal and tumorigencity. Further, BMP pathway activation confers relative resistance to radiation and temozolomide chemotherapy. Our findings define a quiescent cancer stem cell population in glioblastoma that may be a cellular reservoir for tumor recurrence following cytotoxic therapy.

Details

Title
BMP signaling mediates glioma stem cell quiescence and confers treatment resistance in glioblastoma
Author
Sachdeva, Rohit 1 ; Wu, Megan 1 ; Johnson, Kevin 2   VIAFID ORCID Logo  ; Kim, Hyunsoo 2   VIAFID ORCID Logo  ; Celebre, Angela 3 ; Uswa Shahzad 4 ; Maya Srikanth Graham 5 ; Kessler, John A 6 ; Chuang, Jeffrey H 2   VIAFID ORCID Logo  ; Karamchandani, Jason 7 ; Bredel, Markus 8 ; Verhaak, Roel 2   VIAFID ORCID Logo  ; Das, Sunit 9   VIAFID ORCID Logo 

1  Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Kids, Toronto, Ontario, Canada 
2  The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA 
3  Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Kids, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada 
4  Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Kids, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada 
5  Department of Neurology, Memorial Sloan Kettering, New York City, New York, USA; Department of Neurology and Institute for Stem Cell Medicine, Northwestern University, Chicago, Illinois, USA 
6  Department of Neurology and Institute for Stem Cell Medicine, Northwestern University, Chicago, Illinois, USA 
7  Department of Laboratory Medicine, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada 
8  Department of Radiation Oncology, University of Alabama-Birmingham, Birmingham, Alabama, USA 
9  Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Kids, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Division of Neurosurgery, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada 
Pages
1-14
Publication year
2019
Publication date
Oct 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-51270-1
ProQuest document ID
2303724468
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.