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 1

CD109 is associated with STAT3 phosphorylation and malignancy in glioblastoma.

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CD109 is associated with STAT3 phosphorylation and malignancy in gliobla...
(A) Representative micrographs of negative, low, moderate, and high CD109 IHC staining of clinical glioma samples. Scale bar: 50 μm. (B) Association of CD109 expression with tumor grade (n = 346). P < 0.007, χ2 test. See also Supplemental Table 1. (C) Kaplan-Meier survival analysis based on CD109 expression. The median value was used as cutoff; CD109hi (n = 118), red line, and CD109lo (n = 122), black line. P = 0.024, log-rank test. (D and E) Association of CD109 expression with p-STAT3 (n = 78; P = 0.002) (D) and Ki-67 (n = 173; P = 0.041) (E) in glioblastomas, χ2 test. See also Supplemental Table 3. (F) CD109 mRNA expression between glioblastoma (n = 489) and nontumor specimens (n = 10) in the TCGA glioblastoma (TCGA GBM) data set. P < 0.001, Tukey’s post hoc test. (G) Heatmap shows CD109 mRNA expression between different glioblastoma subtypes across several glioblastoma data sets: mesenchymal (MES), classical (CL), and proneural (PN). (H) Heatmap shows mRNA expression levels of CD109, IL6ST, STAT3, and IL-6 between glioblastoma cell lines across different subtypes in the HGCC data set.