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

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 5

CD109 silencing profoundly hampers glioblastoma growth in vivo.

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CD109 silencing profoundly hampers glioblastoma growth in vivo. Represen...
Representative micrographs of coronal sections of tumor-bearing animal brains after implantation of nontargeted control or CD109-silenced BT12 (A), BT13 (B), BT18 (C), or ZH305 (D) GSCs. Frozen sections were immunostained with anti-human vimentin (green). Nuclei were counterstained with DAPI (white). Scale bar: 2 mm. Quantification of the BT12 (E) and BT13 (F) tumor volume, number of BT12 (G) and BT13 (H) satellite tumors, and number of single invasive BT12 (I) and BT13 (J) cells of control and CD109-silenced BT12 (n = 10) and BT13 (n = 10) xenografts. Quantification of the BT18 (K) and ZH305 (L) tumor area and number of single invasive BT18 (M) and ZH305 (N) cells of control and CD109-silenced BT18 (n = 7) and ZH305 (n = 6) xenografts. Quantification of the number of Ki-67+ BT12 (O) and BT13 (P) tumor cells and number or OLIG2+ BT12 (Q) and BT13 (R) tumor cells of control and CD109-silenced BT12 (n = 10) and BT13 (n = 10) xenografts. Western blot analysis of expression of indicated proteins from the whole brain section extracts of BT12 (S) and BT13 (T) control and CD109-silenced BT12 (n = 3) and BT13 (n = 3) xenografts. (U) Representative micrographs of BT12 xenografts immunostained with anti–PDGFR-α (white), anti-human vimentin (green), and podocalyxin (red). Nuclei were counterstained with DAPI (blue). Scale bar: 100 μm. (V) Representative micrographs of BT12 xenografts immunostained with anti-NG2 (red, arrows) and anti-human nuclear marker (NUMA, green). Nuclei were counterstained with DAPI (blue). Scale bars: 1 mm or 25 μm as indicated. (W) Quantification of the number of PDGFR-α+ cells in control and CD109-silenced BT12 (n = 10) xenografts. (X) Quantification of the number of NG2+ cells in control and CD109-silenced BT12 (n = 10) xenografts. P values were calculated using unpaired 2-tailed t test.