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KIAA1549-BRAF Expression Establishes A Permissive Tumor Microenvironment Through Nfκb-Mediated CCL2 Production
Neoplasia
  • Ran Chen
  • Chanel Keoni
  • Christopher A. Waker
  • Robert M. Lober, Wright State University
  • Robert M. Lober, Wright State University
  • Yihsien Chen
  • David H. Gutmann
Document Type
Article
Publication Date
1-1-2019
Abstract

KIAA1549-BRAF is the most frequently identified genetic mutation in sporadic pilocytic astrocytoma (PA), creating a fusion BRAF (f-BRAF) protein with increased BRAF activity. Fusion-BRAF-expressing neural stem cells (NSCs) exhibit increased cell growth and can generate glioma-like lesions following injection into the cerebella of naïve mice. Increased Iba1+ monocyte (microglia) infiltration is associated with murine f-BRAF-expressing NSC-induced glioma-like lesion formation, suggesting that f-BRAF-expressing NSCs attract microglia to establish a microenvironment supportive of tumorigenesis. Herein, we identify Ccl2 as the chemokine produced by f-BRAF-expressing NSCs, which is critical for creating a permissive stroma for gliomagenesis. In addition, f-BRAF regulation of Ccl2 production operates in an ERK- and NFκB-dependent manner in cerebellar NSCs. Finally, Ccr2-mediated microglia recruitment is required for glioma-like lesion formation in vivo, as tumor do not form in Ccr2-deficient mice following f-BRAF-expressing NSC injection. Collectively, these results demonstrate that f-BRAF expression creates a supportive tumor microenvironment through NFκB-mediated Ccl2 production and microglia recruitment.

Comments
© 2018 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
DOI
10.1016/j.neo.2018.11.007
Citation Information
Ran Chen, Chanel Keoni, Christopher A. Waker, Robert M. Lober, et al.. "KIAA1549-BRAF Expression Establishes A Permissive Tumor Microenvironment Through Nfκb-Mediated CCL2 Production" Neoplasia Vol. 76 Iss. 1 (2019) p. 52 - 60 ISSN: 1522-8002
Available at: http://works.bepress.com/robert-lober/27/