HBEGF promotes gliomagenesis in the context of Ink4a/Arf and Pten loss

C. H. Shin, J. P. Robinson, J. A. Sonnen, A. E. Welker, D. X. Yu, M. W. VanBrocklin, S. L. Holmen

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) is a ligand for the EGF receptor (EGFR), one of the most commonly amplified receptor tyrosine kinases (RTKs) in glioblastoma (GBM). While HBEGF has been found to be expressed in a subset of malignant gliomas, its sufficiency for glioma initiation has not been evaluated. In this study, we demonstrate that HBEGF can initiate GBM in mice in the context of Ink4a/Arf and Pten loss, and that these tumors are similar to the classical GBM subtype observed in patients. Isogenic astrocytes from these mice showed activation not only of Egfr but also the RTK Axl in response to HBEGF stimulation. Deletion of either Egfr or Axl decreased the tumorigenic properties of HBEGF-transformed cells; however, only EGFR was able to rescue the phenotype in cells lacking both RTKs indicating that Egfr is required for activation of Axl in this context. Silencing of HBEGF in vivo resulted in tumor regression and significantly increased survival, suggesting that HBEGF may be a clinically relevant target.

Original languageEnglish (US)
Pages (from-to)4610-4618
Number of pages9
JournalOncogene
Volume36
Issue number32
DOIs
StatePublished - Aug 10 2017

Bibliographical note

Funding Information:
We thank the members of the VanBrocklin, McMahon and Holmen labs, as well as E Holland, R DePinho and M Bosenberg for providing mouse strains, reagents and advice. We thank the Huntsman Cancer Institute (HCI) Vivarium staff for assistance. We thank Tim Parnell for his bioinformatics expertise. We acknowledge the use of the Mutation Generation and Detection Core, the DNA Synthesis Core, the DNA Sequencing Core and the Small Animal Imaging Core supported by P30CA042014 awarded to HCI from the National Cancer Institute (NCI). We also acknowledge use of the HCI Shared Resources for high-throughput genomics and bioinformatics analysis, glass wash and research histology. This work was supported by the National Institute of Neurological Disorders and Stroke (NIH R01NS073870, to SLH) and the NCI (NIH F30CA203096, to CHS).

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