KIAA1549-BRAF Expression Establishes a Permissive Tumor Microenvironment Through NFκB-Mediated CCL2 Production.

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.

• Authors: Ran Chen, Chanel Keoni, Christopher A Waker, Robert M Lober, Yi-Hsien Chen, David H Gutmann
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 21 Issue 1 Pg. 52-60 (01 2019) ISSN: 1476-5586 [Electronic] United States
• PMID: 30504064 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• BRAF-KIAA1549 fusion protein, human
• CCL2 protein, human
• Chemokine CCL2
• NF-kappa B
• Oncogene Proteins, Fusion

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Chemokine CCL2 (biosynthesis)
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Male
• Mice
• Mice, Transgenic
• NF-kappa B (metabolism)
• Neoplasms (genetics, metabolism, pathology)
• Oncogene Proteins, Fusion (genetics)
• Tumor Microenvironment (genetics)