CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity
Pauliina Filppu, … , Vadim Le Joncour, Pirjo Laakkonen
Pauliina Filppu, … , Vadim Le Joncour, Pirjo Laakkonen
Published May 10, 2021
Citation Information: JCI Insight. 2021;6(9):e141486. https://doi.org/10.1172/jci.insight.141486.
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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 3

CD109-GP130 interaction promotes activation of the STAT3 pathway.

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CD109-GP130 interaction promotes activation of the STAT3 pathway. (A) qR...
(A) qRT-PCR analysis of IL6R and IL6ST mRNA levels in GSCs. Data are presented as mean ± SD. (B and C) Western blot analyses of p-STAT3 levels in CD109-silenced and nontargeted control GSCs after stimulation with IL-6 cytokine (50 ng/mL) for 15 and 30 minutes. (D) qRT-PCR analysis of IL6ST mRNA levels in CD109-silenced and nontargeted control GSCs. Data are presented as mean ± SEM. *P < 0.05; ****P < 0.0001, unpaired 2-tailed t test. (E) Western blot analysis of GP130 expression after CD109 silencing in GSCs of different glioblastoma subtypes. (F and G) Western blot analyses of CD109 expression and p-STAT3 levels in GP130-silenced and nontargeted control GSCs. (H) Co-IP analysis of CD109. GSC whole-cell extracts were subjected to immunoprecipitation with an anti-GP130 antibody or appropriate IgG control followed by Western blotting with an anti-CD109 antibody. Inputs are indicated. (I and J) Representative micrographs of PLA in GSCs using anti-CD109 and anti-GP130 antibodies. Appropriate IgG controls served as negative controls. Red indicates specific interaction signal. Nuclei were counterstained with DAPI (blue). Scale bar: 20 μm. (K and L) Quantification of PLA signal per cell (DAPI). Data are presented as mean ± SD. **P < 0.01; ****P < 0.0001, 1-way ANOVA with Tukey’s multiple comparisons test. Data are from n = 3 (A–G) and n = 2 (H–L) independent experiments. Representative Western blots are shown, where β-tubulin served as a loading control.