Abstract
Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM. In this study, we present novel evidence that BIRC3 has an essential noncanonical role in GBM self-renewal and stemness reprogramming. We demonstrate that BIRC3 drives stemness reprogramming of human GBM cell lines, mouse GBM cell lines and patient-derived GBM stem cells (GSCs) through regulation of BMP4 signaling axis. Specifically, BIRC3 induces stemness reprogramming in GBM through downstream inactivation of BMP4 signaling. RNA-Seq interrogation of the stemness reprogramming hypoxic (pseudopalisading necrosis and perinecrosis) niche in GBM patient tissues further validated the high BIRC3/low BMP4 expression correlation. BIRC3 knockout upregulated BMP4 expression and prevented stemness reprogramming of GBM models. Furthermore, siRNA silencing of BMP4 restored stemness reprogramming of BIRC3 knockout in GBM models. In vivo silencing of BIRC3 suppressed tumor initiation and progression in GBM orthotopic intracranial xenografts. The stemness reprograming of both GSCs and non-GSCs populations highlights the impact of BIRC3 on intra-tumoral cellular heterogeneity GBM. Our study has identified a novel function of BIRC3 that can be targeted to reverse stemness programming of GBM.
Highlights
Glioblastoma (GBM) is a highly resistant and lethal brain cancer with limited treatment options
In order to evaluate the impact of BIRC3 on stemness reprogramming, we evaluated the impact of BIRC3 gain-of-function and loss-of-function on the ability of GBM cells to form neurospheres
Identifying mechanisms of GBM stemness is very important in advancing our understanding and targeting of GBM
Summary
Glioblastoma (GBM) is a highly resistant and lethal brain cancer with limited treatment options. A classic hallmark of GBM is the rapid acquisition of therapeutic resistance leading to lethality. Stemness adaptation is a leading hypothesis for therapeutic failures in GBM [2]. GBM cells with stem-like phenotype known as GBM stem-like cells or GBM stem cells (GSCs) drive resistance to RT and TMZ treatment [3]. Evidence from GBM mouse models implicates GSCs in the repopulation of tumors following TMZ and RT treatment [4]. GSCs exploit normal neural stem cell developmental transcription mechanisms towards tumorigenesis adaptation [12,13,14]
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