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Snail depletes the tumorigenic potential of glioblastoma
1Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.
Abstract:
Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic potential.
Insights
Bone morphogenetic protein (BMP) signaling regulates glioma-initiating cells (GICs) in glioblastoma. This study reveals Snail acts downstream of BMP, promoting invasion but reducing GIC tumor-forming capacity.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain cancer.
- Glioma-initiating cells (GICs) drive tumor growth and resistance to therapy.
- Bone morphogenetic protein (BMP) signaling is known to suppress GICs.
Purpose of the Study:
- To elucidate the molecular mechanisms by which BMP signaling affects GICs.
- To investigate the role of the transcriptional regulator Snail in GBM.
- To determine how Snail influences GBM cell invasion and tumorigenicity.
Main Methods:
- Studied BMP-induced Smad-dependent Snail expression in GBM cells.
- Utilized Snail silencing and overexpression in GBM models.
- Assessed GBM cell migration and invasiveness.
- Evaluated gliomasphere formation and tumor growth in vivo using a mouse xenograft model.
Main Results:
- BMP signaling rapidly and sustainably induces Smad-dependent Snail expression.
- Snail silencing reduced GBM cell migration.
- Snail overexpression increased GBM invasiveness in vivo.
- Surprisingly, Snail reduced GBM's ability to form gliomaspheres and tumors in vivo.
Conclusions:
- Snail acts downstream of BMP signaling in GBM.
- Snail promotes GBM cell invasion while diminishing tumorigenic potential.
- This suggests a dissociation between GBM invasiveness and GIC-driven tumor growth.
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