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; Paula Y.P. Lam

doi:10.1038/s41467-017-01392-9

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, Paula Y.P. Lam

Research output: Contribution to journal › Article

19 Scopus citations

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.

Original language	English (US)
Article number	1913
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01392-9
State	Published - Dec 1 2017

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Newman, J. P., Wang, G. Y., Arima, K., Guan, S. P., Waters, M. R., Cavenee, W. K., Pan, E., Aliwarga, E., Chong, S. T., Kok, C. Y. L., Endaya, B. B., Habib, A. A., Horibe, T., Ng, W. H., Ho, I. A. W., Hui, K. M., Kordula, T., & Lam, P. Y. P. (2017). Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme. Nature communications, 8(1), [1913]. https://doi.org/10.1038/s41467-017-01392-9

Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme. / Newman, Jennifer P.; Wang, Grace Y.; Arima, Kazuhiko; Guan, Shou P.; Waters, Michael R.; Cavenee, Webster K.; Pan, Edward; Aliwarga, Edita; Chong, Siao T.; Kok, Catherine Y.L.; Endaya, Berwini B.; Habib, Amyn A.; Horibe, Tomohisa; Ng, Wai H.; Ho, Ivy A.W.; Hui, Kam M.; Kordula, Tomasz; Lam, Paula Y.P.

In: Nature communications, Vol. 8, No. 1, 1913, 01.12.2017.

Research output: Contribution to journal › Article

Newman, JP, Wang, GY, Arima, K, Guan, SP, Waters, MR, Cavenee, WK, Pan, E, Aliwarga, E, Chong, ST, Kok, CYL, Endaya, BB, Habib, AA, Horibe, T, Ng, WH, Ho, IAW, Hui, KM, Kordula, T & Lam, PYP 2017, 'Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme', Nature communications, vol. 8, no. 1, 1913. https://doi.org/10.1038/s41467-017-01392-9

Newman, Jennifer P. ; Wang, Grace Y. ; Arima, Kazuhiko ; Guan, Shou P. ; Waters, Michael R. ; Cavenee, Webster K. ; Pan, Edward ; Aliwarga, Edita ; Chong, Siao T. ; Kok, Catherine Y.L. ; Endaya, Berwini B. ; Habib, Amyn A. ; Horibe, Tomohisa ; Ng, Wai H. ; Ho, Ivy A.W. ; Hui, Kam M. ; Kordula, Tomasz ; Lam, Paula Y.P. / Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme. In: Nature communications. 2017 ; Vol. 8, No. 1.

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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.",

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