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 4

Loss of CD109 induces a compensatory phenotypic shift to an AC-like state and sensitizes the cells to chemotherapy.

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Loss of CD109 induces a compensatory phenotypic shift to an AC-like stat...
(A and B) qRT-PCR analysis of MAP2, GALC, and GFAP mRNA levels in CD109-silenced and nontargeted GSCs at day 11. Data are presented as mean ± SEM. **P < 0.01; ****P < 0.0001, 2-way ANOVA with Dunnett’s multiple comparisons test. (C) Heatmap shows increased expression of AC-like genes after CD109 silencing at day 11. Data are presented as fold change relative to control. (D and E) qRT-PCR analysis of CL subtype genes in CD109-silenced and nontargeted GSCs at d11. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, unpaired 2-tailed t test. (F) Cell viability of CD109-silenced and nontargeted GSCs at the indicated time points. Data are presented as mean ± SD. *P < 0.05; **P < 0.01, 1-way ANOVA with Kruskal-Wallis post hoc test. (G and H) Immunofluorescence staining of cleaved caspase-3 (green) and F-actin (red) in CD109-silenced and nontargeting control GSCs in 3D fibrin matrix at day 15. Nuclei were counterstained with DAPI (blue). Scale bar: 100 μm. (I) Box-and-whisker plot shows cell viability of CD109-silenced and nontargeting control GSCs after treatment with 250 μM of TMZ for 4 days. Data were normalized to the corresponding vehicle control. ****P < 0.0001, nonparametric Mann-Whitney U test (BT12) and unpaired 2-tailed t test (BT13 and S24). (J) Box-and-whisker plot shows cell viability after treatment with Stattic or combination of Stattic and TMZ. Data were normalized to the corresponding vehicle control. *P < 0.05; **P < 0.01, nonparametric Mann-Whitney U test. Box plots represent the first quartile, median, and third quartile, with whiskers indicating minimum and maximum values. Data are from n = 3 (A, B, and D–J) independent experiments.