SLUG Directs the Precursor State of Human Brain Tumor Stem Cells.

Charles Chesnelong,Xiaoguang Hao,Alice Yijun Wang,Orsolya Cseh,H Artee Luchman,Samuel Weiss

doi:10.3390/cancers11111635

Charles Chesnelong, Xiaoguang Hao + Show 4 more

Open Access

https://doi.org/10.3390/cancers11111635

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Journal: Cancers	Publication Date: Oct 24, 2019
Citations: 15	License type: CC BY 4.0

Affiliation: University of Calgary, Hospital for Sick Children

Abstract

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.

Highlights

Glioblastoma (GBM) is the most common primary adult brain tumor and is characterized by rapid proliferation, widespread invasion, and aggressive behavior
We demonstrate that a STAT3/SLUG-driven process promotes a more aggressive progenitor-like precursor state in brain tumor stem cells (BTSCs) and that this transition is associated with recurrence in GBM
STAT3 did not appear to directly regulate TWIST, a well characterized transcriptional target of STAT3, Surprisingly, STAT3 did not appear to directly regulate TWIST, a well characterized transcriptional nor SNAIL, ZEB1, or ZEB2 (Figure 3I). These results demonstrate that SLUG is a transcriptional target of STAT3, nor SNAIL, ZEB1, or ZEB2 (Figure 3I). These results demonstrate that SLUG is not target of STAT3 but, most importantly, the only epithelial to mesenchymal transition (EMT) transcription factor directly regulated by STAT3 only a transcriptional target of STAT3 but, most importantly, the only EMT transcription factor in BTSCs

Summary

Introduction

Glioblastoma (GBM) is the most common primary adult brain tumor and is characterized by rapid proliferation, widespread invasion, and aggressive behavior. Radiation, and chemotherapy, GBM invariably recurs resulting in a dismal 5% survival rate at five years [1]. GBM subtypes: proneural, neural, classical, and mesenchymal [2]. While there is a lack of consensus on the frequency and clinical relevance of this phenomenon, a proneural to mesenchymal transition (PMT) has been described in GBM upon recurrence [3]. STAT3 is a pro-survival and pro-inflammatory transcription factor abnormally active in a multitude of cancers, including GBM, where it has emerged as a master regulator of tumorigenesis and a mediator of therapeutic resistance [4]. Is STAT3 one of the key transcription factors linked

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