Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme

Jennifer P. Newman, Grace Y. Wang, Kazuhiko Arima, Shou P. Guan, Michael R. Waters, Webster K. Cavenee, Edward Pan, Edita Aliwarga, Siao T. Chong, Catherine Y. L. Kok, Berwini B. Endaya, Amyn A. Habib, Tomohisa Horibe, Wai H. Ng, Ivy A. W. Ho, Kam M. Hui, Tomasz Kordula and Paula Y. P. Lam ()
Additional contact information
Jennifer P. Newman: National Cancer Centre
Grace Y. Wang: National Cancer Centre
Kazuhiko Arima: Saga Medical School
Shou P. Guan: National Cancer Centre
Michael R. Waters: Virginia Commonwealth University
Webster K. Cavenee: Ludwig Institute for Cancer Research
Edward Pan: University of Texas Southwestern Medical Center
Edita Aliwarga: National Cancer Centre
Siao T. Chong: National Cancer Centre
Catherine Y. L. Kok: National Cancer Centre
Berwini B. Endaya: Griffith University
Amyn A. Habib: University of Texas Southwestern Medical Center and the North Texas VA Medical Center
Tomohisa Horibe: Kyoto University School of Public Health
Wai H. Ng: National Neuroscience Institute
Ivy A. W. Ho: National Cancer Centre
Kam M. Hui: National Cancer Centre
Tomasz Kordula: Virginia Commonwealth University
Paula Y. P. Lam: National Cancer Centre

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract The interleukin-13 receptor alpha2 (IL-13Rα2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established. Here we report that IL-13Rα2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Rα2 promotes GBM cell proliferation in vitro and in vivo. Mechanistically, the cytoplasmic domain of IL-13Rα2 specifically binds to EGFRvIII, and this binding upregulates the tyrosine kinase activity of EGFRvIII and activates the RAS/RAF/MEK/ERK and STAT3 pathways. Our findings support the “To Go or To Grow” hypothesis whereby IL-13Rα2 serves as a molecular switch from invasion to proliferation, and suggest that targeting both receptors with STAT3 signaling inhibitor might be a therapeutic approach for the treatment of GBM.

Date: 2017
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DOI: 10.1038/s41467-017-01392-9

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