Interleukin-13 Receptor Alpha 2 Cooperates with EGFRvIII Signaling to Promote Glioblastoma Multiforme

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Dec 6

PMID 29203859

Citations 43

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Pooled screening for CAR function identifies novel IL-13Rα2-targeted CARs for treatment of glioblastoma.

Gordon K, Perez C, Garmilla A, Lam M, Aw J, Datta A J Immunother Cancer. 2025; 13(2).

PMID: 39933837 PMC: 11815465. DOI: 10.1136/jitc-2024-009574.

Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy.

Logun M, Wang X, Sun Y, Bagley S, Li N, Desai A Cell Stem Cell. 2024; 32(2):181-190.e4.

PMID: 39657679 PMC: 11808387. DOI: 10.1016/j.stem.2024.11.010.

Armored bicistronic CAR T cells with dominant-negative TGF-β receptor II to overcome resistance in glioblastoma.

Li N, Rodriguez J, Yin Y, Logun M, Zhang L, Yu S Mol Ther. 2024; 32(10):3522-3538.

PMID: 39086131 PMC: 11489531. DOI: 10.1016/j.ymthe.2024.07.020.

Increased Muc5AC and Decreased Ciliated Cells in Severe Asthma Partially Restored by Inhibition of IL-4Rα Receptor.

Boomer J, Choi J, Alsup A, McGregor M, Lieu J, Johnson C Am J Respir Crit Care Med. 2024; 210(12):1409-1420.

PMID: 38935626 PMC: 11716027. DOI: 10.1164/rccm.202307-1266OC.

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives.

Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y J Hematol Oncol. 2024; 17(1):31.

PMID: 38720342 PMC: 11077829. DOI: 10.1186/s13045-024-01544-7.

References

Fan Q, Cheng C, Gustafson W, Charron E, Zipper P, Wong R . EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell. 2013; 24(4):438-49. PMC: 3819146. DOI: 10.1016/j.ccr.2013.09.004. View

Pelloski C, Ballman K, Furth A, Zhang L, Lin E, Sulman E . Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 2007; 25(16):2288-94. DOI: 10.1200/JCO.2006.08.0705. View

Liu H, Jacobs B, Liu J, Prayson R, Estes M, Barnett G . Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. Cancer Immunol Immunother. 2000; 49(6):319-24. PMC: 11036967. DOI: 10.1007/s002620000110. View

Shibasaki N, Yamasaki T, Kanno T, Arakaki R, Sakamoto H, Utsunomiya N . Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma. PLoS One. 2015; 10(6):e0130980. PMC: 4482605. DOI: 10.1371/journal.pone.0130980. View

Debinski W, Gibo D . Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol Med. 2000; 6(5):440-9. PMC: 1949955. View

Marziali G, Signore M, Buccarelli M, Grande S, Palma A, Biffoni M . Metabolic/Proteomic Signature Defines Two Glioblastoma Subtypes With Different Clinical Outcome. Sci Rep. 2016; 6:21557. PMC: 4746700. DOI: 10.1038/srep21557. View

Holland E, Hively W, DePinho R, Varmus H . A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 1998; 12(23):3675-85. PMC: 317252. DOI: 10.1101/gad.12.23.3675. View

Lal A, Glazer C, Martinson H, Friedman H, Archer G, Sampson J . Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Res. 2002; 62(12):3335-9. View

Jahani-Asl A, Yin H, Soleimani V, Haque T, Luchman H, Chang N . Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci. 2016; 19(6):798-806. PMC: 4984527. DOI: 10.1038/nn.4295. View

10.

Puri R, Leland P, Obiri N, Husain S, Kreitman R, Haas G . Targeting of interleukin-13 receptor on human renal cell carcinoma cells by a recombinant chimeric protein composed of interleukin-13 and a truncated form of Pseudomonas exotoxin A (PE38QQR). Blood. 1996; 87(10):4333-9. View

11.

Liu T, Tatter S, Willingham M, Yang M, Hu J, Frankel A . Growth factor receptor expression varies among high-grade gliomas and normal brain: epidermal growth factor receptor has excellent properties for interstitial fusion protein therapy. Mol Cancer Ther. 2003; 2(8):783-7. View

12.

Brown C, Alizadeh D, Starr R, Weng L, Wagner J, Naranjo A . Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med. 2016; 375(26):2561-9. PMC: 5390684. DOI: 10.1056/NEJMoa1610497. View

13.

Parsons D, Jones S, Zhang X, Cheng-Ho Lin J, Leary R, Angenendt P . An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321(5897):1807-12. PMC: 2820389. DOI: 10.1126/science.1164382. View

14.

Saikali S, Avril T, Collet B, Hamlat A, Bansard J, Drenou B . Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy. J Neurooncol. 2006; 81(2):139-48. DOI: 10.1007/s11060-006-9220-3. View

15.

Arima K, Sato K, Tanaka G, Kanaji S, Terada T, Honjo E . Characterization of the interaction between interleukin-13 and interleukin-13 receptors. J Biol Chem. 2005; 280(26):24915-22. DOI: 10.1074/jbc.M502571200. View

16.

Husain S, Joshi B, Puri R . Interleukin-13 receptor as a unique target for anti-glioblastoma therapy. Int J Cancer. 2001; 92(2):168-75. DOI: 10.1002/1097-0215(200102)9999:9999<::aid-ijc1182>3.0.co;2-n. View

17.

Rahaman S, Vogelbaum M, Haque S . Aberrant Stat3 signaling by interleukin-4 in malignant glioma cells: involvement of IL-13Ralpha2. Cancer Res. 2005; 65(7):2956-63. DOI: 10.1158/0008-5472.CAN-04-3592. View

18.

Bos P, Zhang X, Nadal C, Shu W, Gomis R, Nguyen D . Genes that mediate breast cancer metastasis to the brain. Nature. 2009; 459(7249):1005-9. PMC: 2698953. DOI: 10.1038/nature08021. View

19.

Nishikawa R, Ji X, Harmon R, LAZAR C, Gill G, Cavenee W . A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A. 1994; 91(16):7727-31. PMC: 44475. DOI: 10.1073/pnas.91.16.7727. View

20.

Phillips H, Kharbanda S, Chen R, Forrest W, Soriano R, Wu T . Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006; 9(3):157-73. DOI: 10.1016/j.ccr.2006.02.019. View