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      OS1.5 Harnessing soluble LRIG1 for pan-RTK targeting in glioblastoma

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          Abstract

          Introduction

          The role of receptor tyrosine kinases (RTKs) in glioblastoma is widely acknowledged. However, therapies based on RTK targeting have been continuously unsuccessful in GBM patients, highlighting the complexity of RTK signaling and biology. LRIG1 (Leucine-rich Repeats and ImmunoGlobulin domains protein 1) was identified as an endogenous inhibitor of epidermal growth factor receptor (EGFR) and other RTKs, and was confirmed as a tumor suppressor in various cancer types. We previously identified the soluble form of LRIG1 as a potent inhibitor of GBM growth in vivo, irrespective of EGFR status. Here, we aim to shed light on the molecular mechanisms underlying its anti-cancer activity.

          Material and Methods

          We used GBM cells overexpressing EGFRvIII, with or without soluble LRIG1 overexpression. In parallel, we generated a recombinant human soluble LRIG1 protein (rh-sLRIG1) by expressing LRIG1 ectodomain in insect cells via baculovirus infection and subsequent His-tag purification. rh-sLRIG1 was applied in the medium of classical GBM cell lines and patient-derived GBM stem-like cells. Applying a variety of cell-based assays, cell proliferation, migration, cell morphology, as well as protein expression and protein-protein interactions were investigated.

          Results

          We confirmed that sLRIG1 efficiently reduced proliferation and invasion capacities of GBM cells, and modulated cytoskeleton proteins and cell shape. Inhibition of cell proliferation by sLRIG1 was independent of EGFR expression levels in GBM cells and interestingly, rh-sLRIG1 treatment was associated with downregulation of AXL, which constitutes a newly-identified regulatory function of LRIG1. We are currently addressing the impact of the LRIG1-AXL signaling axis on GBM invasion and resistance to EGFR inhibition.

          Conclusion

          We identified AXL as a novel LRIG1 target and provide evidence for the potential therapeutic application of recombinant sLRIG1 in the inhibition of growth factor signaling in GBM.

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          Author and article information

          Journal
          Neuro Oncol
          Neuro-oncology
          neuonc
          Neuro-Oncology
          Oxford University Press (US )
          1522-8517
          1523-5866
          September 2018
          19 September 2018
          : 20
          : Suppl 3 , 13th Meeting of the European Association of Neurooncology October 10-14, 2018 Stockholm, Sweden
          : iii218
          Affiliations
          [1 ]Luxembourg Institute of Health, Luxembourg, Luxembourg
          [2 ]Johannes Gutenberg University, Mainz, Germany
          [3 ]German Cancer Research Center (DKFZ), Heidelberg, Germany
          [4 ]KG Jebsen Brain Tumour Research Center, Bergen, Norway
          Article
          PMC6144038 PMC6144038 6144038 noy139.011
          10.1093/neuonc/noy139.011
          6144038
          © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

          This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

          Page count
          Pages: 1
          Categories
          Oral Presentations
          OS1 Basic science and Pathology

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