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CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity
Pauliina Filppu, Jayendrakishore Tanjore Ramanathan, Kirsi J. Granberg, Erika Gucciardo, Hannu Haapasalo, Kaisa Lehti, Matti Nykter, Vadim Le Joncour, Pirjo Laakkonen
Pauliina Filppu, Jayendrakishore Tanjore Ramanathan, Kirsi J. Granberg, Erika Gucciardo, Hannu Haapasalo, Kaisa Lehti, Matti Nykter, Vadim Le Joncour, Pirjo Laakkonen
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Research Article Oncology Stem cells

CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity

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Abstract

Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumors. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we report CD109/STAT3 axis as crucial for the maintenance of stemness and tumorigenicity of GSCs and as a mediator of chemoresistance. Mechanistically, CD109 physically interacts with glycoprotein 130 to promote activation of the IL-6/STAT3 pathway in GSCs. Genetic depletion of CD109 abolished the stemness and self-renewal of GSCs and impaired tumorigenicity. Loss of stemness was accompanied with a phenotypic shift of GSCs to more differentiated astrocytic-like cells. Importantly, genetic or pharmacologic targeting of CD109/STAT3 axis sensitized the GSCs to chemotherapy, suggesting that targeting CD109/STAT3 axis has potential to overcome therapy resistance in glioblastoma.

Authors

Pauliina Filppu, Jayendrakishore Tanjore Ramanathan, Kirsi J. Granberg, Erika Gucciardo, Hannu Haapasalo, Kaisa Lehti, Matti Nykter, Vadim Le Joncour, Pirjo Laakkonen

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Figure 6

CD109 silencing modifies glioblastoma stroma.

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CD109 silencing modifies glioblastoma stroma.
(A) Representative microgr...
(A) Representative micrographs of BT12 xenografts immunostained with anti–collagen IV (green) and anti-podocalyxin (red). Nuclei were counterstained with DAPI (blue). Scale bar: 40 μm. Arrows indicate empty basement membrane sleeves devoid of endothelium. (B) Quantification of collagen IV+/PODXL– empty sleeves in control and CD109-silenced BT12 xenografts (n = 10). (C) Representative micrographs of BT12 xenografts immunostained with anti-human vimentin (green) and anti-mouse CD31 (red). Nuclei were counterstained with DAPI (blue). Scale bars: 2 mm or 40 μm as indicated. Quantification of the average tumor blood vessel size (D) and density (E) in control and CD109-silenced BT12 xenografts (n = 10). (F) Quantification of the secreted ANG1 and ANG2 levels from the cell culture supernatants of CD109-silenced and nontargeted control BT12 GSCs (n = 2). (G) Expression of ANGPT1 and ANGPT2 mRNA levels determined by total RNA-Seq in CD109-silenced and nontargeted BT12 GSCs at the indicated time points. (H) Representative micrographs of BT12 xenografts immunostained with anti-human NUMA (green) and anti-NG2 (red). Nuclei were counterstained with DAPI (blue). Scale bars: 2 mm or 40 μm as indicated. (I) Representative micrographs of BT12 xenografts immunostained with anti–α-SMA (green) and anti-CD31 (red). Nuclei were counterstained with DAPI (blue). Scale bar: 40 μm. (J) Quantification of the α-SMA+ tumor pericytes in control and CD109-silenced BT12 xenografts (n = 10). (K) Representative micrographs of BT12 xenografts immunostained with anti-NG2 (green) and anti-CD31 (red). Nuclei were counterstained with DAPI (blue). Scale bar: 40 μm. (L) Quantification of the pericyte coverage in control and CD109-silenced BT12 xenografts (n = 10). P values were calculated by using the unpaired 2-tailed t test except for F and G, where a t test with Mann-Whitney post hoc test was used.

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