TY - JOUR
T1 - CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity
AU - Filppu, Pauliina
AU - Ramanathan, Jayendrakishore Tanjore
AU - Granberg, Kirsi J.
AU - Gucciardo, Erika
AU - Haapasalo, Hannu
AU - Lehti, Kaisa
AU - Nykter, Matti
AU - Le Joncour, Vadim
AU - Laakkonen, Pirjo
N1 - Funding Information:
We would like to thank Maija Pfenniger for technical supervision and Päivi Peltokangas for technical assistance in IHC. We would like to thank Suvi Lehtipuro for assistance in bioinformatic analyses. H2 cell line was a gift from Seppo Meri. We thank the Biomedicum Imaging Unit (University of Helsinki), Genome Biology Unit (HiLIFE, University of Helsinki and Biocenter Finland), Biomedicum Functional Genomics Unit (HiLIFE, University of Helsinki), and Laboratory Animal Center (HiLIFE, University of Helsinki) for providing professional services. This work was supported by grants from the Finnish Cancer Foundation and Jane & Aatos Erkko Foundation (to PL); K. Albin Johanssons stiftelse, Finnish Cultural Foundation, the Finnish Cancer Foundation, Maud Kuistila Memorial Foundation, the Ida Montin Foundation, and the Biomedicum Helsinki Foundation (to PF); and the Academy of Finland (grant 321867), K. Albin Johanssons stiftelse, and Magnus Ehrnrooth Foundation (to VLJ). PF has been supported by the Doctoral Programme in Biomedicine, University of Helsinki. Open access was funded by Helsinki University Library.
Publisher Copyright:
© 2021, Filppu et al.
PY - 2021/5/10
Y1 - 2021/5/10
N2 - 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.
AB - 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.
U2 - 10.1172/jci.insight.141486
DO - 10.1172/jci.insight.141486
M3 - Article
C2 - 33986188
AN - SCOPUS:85105905160
VL - 6
IS - 9
M1 - e141486
ER -