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
View: Text | PDF
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

×

Figure 2

CD109/STAT3 axis maintains glioblastoma cell stemness.

Options: View larger image (or click on image) Download as PowerPoint
CD109/STAT3 axis maintains glioblastoma cell stemness. (A) Heatmap shows...
(A) Heatmap shows the classification of patient-derived GSCs and the H2 cell line based on their dominant transcriptional subtype: mesenchymal-like (MES), classical-like (CL), and proneural-like (PN). (B and C) Western blot analyses of CD109, SOX2, and OLIG2 expression in GSCs and differentiated glioma cells cultured in FBS-containing medium at the indicated time points. (D) Western blot analysis of CD109 expression and p-STAT3 levels in GSCs of different glioblastoma subtypes. (E and F) Western blot analyses of SOX2 and OLIG2 expression in CD109-silenced GSCs and nontargeted controls at the indicated time points. (G and H) Real-time quantitative PCR (qRT-PCR) analysis of GSC marker mRNA levels in CD109-silenced and nontargeted control GSCs at day 11. (I) Cell proliferation of CD109-silenced and nontargeted control GSCs at indicated time points. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001, 2-way ANOVA with Tukey’s multiple comparisons test. (J) Representative micrographs of colony formation in methylcellulose after CD109 silencing. Scale bar: 200 μm. (K and L) Quantification of colonies in methylcellulose. Data are presented as mean ± SD. ****P < 0.0001, 1-way ANOVA with Dunnett’s multiple comparisons test. (M) Representative micrographs of GSC growth in 3D fibrin matrix after CD109 silencing. Scale bar: 200 μm. Inset: original magnification, ×10. See also Supplemental Figure 2D. (N) Cell viability in 3D fibrin matrix at day 15. Data are presented as mean ± SD. ****P < 0.0001, unpaired 2-tailed t test. See also Supplemental Figure 2E. (O) Western blot analysis of p-STAT3 levels after CD109 silencing. Data are from n = 2 (B and C) and n = 3 (D–O) independent experiments. Representative Western blots are shown where β-tubulin served as a loading control.