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Article

SLUG Directs the Precursor State of Human Brain Tumor Stem Cells

1
Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
2
Arthur and Sonia Labatt Brain Tumor Research Center, Developmental and Stem Cell Biology department, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(11), 1635; https://doi.org/10.3390/cancers11111635
Received: 20 September 2019 / Revised: 17 October 2019 / Accepted: 23 October 2019 / Published: 24 October 2019
In glioblastoma (GBM), brain tumor stem cells (BTSCs) encompass heterogenous populations of multipotent, self-renewing, and tumorigenic cells, which have been proposed to be at the root of therapeutic resistance and recurrence. While the functional significance of BTSC heterogeneity remains to be fully determined, we previously distinguished relatively quiescent stem-like precursor state from the more aggressive progenitor-like precursor state. In the present study, we hypothesized that progenitor-like BTSCs arise from stem-like precursors through a mesenchymal transition and drive post-treatment recurrence. We first demonstrate that progenitor-like BTSCs display a more mesenchymal transcriptomic profile. Moreover, we show that both mesenchymal GBMs and progenitor-like BTSCs are characterized by over-activated STAT3/EMT pathways and that SLUG is the primary epithelial to mesenchymal transition (EMT) transcription factor directly regulated by STAT3 in BTSCs. SLUG overexpression in BTSCs enhances invasiveness, promotes inflammation, and shortens survival. Importantly, SLUG overexpression in a quiescent stem-like BTSC line enhances tumorigenesis. Finally, we report that recurrence is associated with SLUG-induced transcriptional changes in both BTSCs and GBM patient samples. Collectively, our findings show that a STAT3-driven precursor state transition, mediated by SLUG, may prime BTSCs to initiate more aggressive mesenchymal recurrence. Targeting the STAT3/SLUG pathway may maintain BTSCs in a quiescent stem-like precursor state, delaying recurrence and improving survival in GBM. View Full-Text
Keywords: glioblastoma (GBM); brain tumor stem cells (BTSC); precursor state; epithelial to mesenchymal transition (EMT); STAT3; SLUG glioblastoma (GBM); brain tumor stem cells (BTSC); precursor state; epithelial to mesenchymal transition (EMT); STAT3; SLUG
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MDPI and ACS Style

Chesnelong, C.; Hao, X.; Cseh, O.; Wang, A.Y.; Luchman, H.A.; Weiss, S. SLUG Directs the Precursor State of Human Brain Tumor Stem Cells. Cancers 2019, 11, 1635. https://doi.org/10.3390/cancers11111635

AMA Style

Chesnelong C, Hao X, Cseh O, Wang AY, Luchman HA, Weiss S. SLUG Directs the Precursor State of Human Brain Tumor Stem Cells. Cancers. 2019; 11(11):1635. https://doi.org/10.3390/cancers11111635

Chicago/Turabian Style

Chesnelong, Charles, Xiaoguang Hao, Orsolya Cseh, Alice Y. Wang, H. A. Luchman, and Samuel Weiss. 2019. "SLUG Directs the Precursor State of Human Brain Tumor Stem Cells" Cancers 11, no. 11: 1635. https://doi.org/10.3390/cancers11111635

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