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

doi:10.1172/jci.insight.141486

CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity

JCI Insight. 2021 May 10;6(9):e141486. doi: 10.1172/jci.insight.141486.

Authors

Pauliina Filppu¹, Jayendrakishore Tanjore Ramanathan¹, Kirsi J Granberg^{2

3}, Erika Gucciardo⁴, Hannu Haapasalo⁵, Kaisa Lehti^{4

6

7}, Matti Nykter², Vadim Le Joncour¹, Pirjo Laakkonen^{1

8}

Affiliations

¹ Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
² Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
³ Science Center, Tampere University Hospital, Tampere, Finland.
⁴ Individualized Drug Therapy Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁵ Department of Pathology, Fimlab Laboratories, Tampere University Hospital and University of Tampere, Tampere, Finland.
⁶ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Biomedical Laboratory Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
⁸ Laboratory Animal Centre, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.

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.

Keywords: Brain cancer; Molecular biology; Molecular pathology; Oncology; Stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / genetics*
Antigens, CD / metabolism
Antineoplastic Agents, Alkylating / therapeutic use
Astrocytoma / genetics*
Astrocytoma / metabolism
Astrocytoma / pathology
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Plasticity / genetics
Cytokine Receptor gp130 / genetics*
Cytokine Receptor gp130 / metabolism
Drug Resistance, Neoplasm / genetics*
Female
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Glioblastoma / genetics*
Glioblastoma / metabolism
Glioblastoma / pathology
Humans
Interleukin-6 / metabolism
Male
Mice
Mice, Nude
Middle Aged
Neoplasm Grading
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Neoplasm Transplantation
Neoplastic Stem Cells / metabolism*
Real-Time Polymerase Chain Reaction
STAT3 Transcription Factor / metabolism*
Signal Transduction
Temozolomide / therapeutic use

Substances

Antigens, CD
Antineoplastic Agents, Alkylating
CD109 protein, human
GPI-Linked Proteins
IL6 protein, human
IL6ST protein, human
Interleukin-6
Neoplasm Proteins
STAT3 Transcription Factor
STAT3 protein, human
Cytokine Receptor gp130
Temozolomide