Journal
CANCER RESEARCH
Volume 78, Issue 24, Pages 6785-6794Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-3551
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Funding
- Alex's Lemonade Stand Foundation [CA-0091339]
- American Brain Tumor Association [BRF1800011]
- NIH [R01CA221969, R01NS091620, P50CA097257, U01CA217864, P30CA82103, T32CA108462]
- Program for Breakthrough Biomedical Research - Sandler Foundation [7028233]
- German Cancer Aid [110663]
- BMBF [01ZX1401B]
- Samuel G. Waxman Cancer Research Foundation [A128431]
- NATIONAL CANCER INSTITUTE [P30CA082103, T32CA108462, R01CA221969, P50CA097257, U01CA217864] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS091620] Funding Source: NIH RePORTER
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Amplification of the EGFR gene and its truncation mutant EGFRvIII are hallmarks of glioblastoma. Although coexpression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood. Here, we show that EGFR and EGFRvIII cooperate to induce macrophage infiltration via upregulation of the chemokine CCL2. EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors coexpressing EGFR and EGFRvIII led to decreased infiltration of macrophages. KRAS was a critical signaling intermediate for EGFR- and EGFRvIII-induced expression of CCL2. Our results illustrate how EGFR and EGFRvIII direct the microenvironment in glioblastoma. Significance: Full-length EGFR and truncated EGFRvIII work through KRAS to upregulate the chemokine CCL2 and drive macrophage infiltration in glioblastoma. (C) 2018 AACR.
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