Plexiform neurofibroma, a benign peripheral nerve tumor, is associated with the biallelic loss of function of the NF1 tumor suppressor in Schwann cells. Here, we show that FLLL32, a small molecule inhibitor of JAK2/STAT3 signaling, reduces neurofibroma growth in mice with conditional, biallelic deletion of Nf1 in the Schwann cell lineage. FLLL32 treatment or Stat3 deletion in tumor cells reduced inflammatory cytokine expression and tumor macrophage numbers in neurofibroma. Although STAT3 inhibition downregulated the chemokines CCL2 and CCL12, which can signal through CCR2 to recruit macrophages to peripheral nerves, deletion of Ccr2 did not improve survival or reduce macrophage numbers in neurofibroma-bearing mice. Interestingly, Iba1+; F4/80+;CD11b+ macrophages accounted for ~20–40% of proliferating cells in untreated tumors. FLLL32 suppressed macrophage proliferation, implicating STAT3-dependent, local proliferation in neurofibroma macrophage accumulation, and decreased Schwann cell proliferation and increased Schwann cell death. The functions of STAT3 signaling in neurofibroma Schwann cells and macrophages, and its relevance as a therapeutic target in neurofibroma, merit further investigation.
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We thank James Fuchs and Jiayuh Lin (The Ohio State University) for providing FLLL32, and the Imaging Resource Center at Cincinnati Children’s Hospital Medical Center (R. Scott Dunn) for MRI Imaging. This work was supported by R01 NS28840 (to NR and JW), and DOD W81XWH-11-1-0057 (to NR), DOD W81XWH-11-1-0259 (to JW), and RNA-Seq by an Agreement with the Neurofibromatosis Therapeutic Acceleration Program (NTAP) at Johns Hopkins University (to NR). JSF was the recipient of 5 F30 NS096796.
Conflict of interest
The authors declare that they have no conflict of interest.
The animal care and use committee of the Cincinnati Children’s Hospital Medical Center approved all animal care and procedures. Human tissues were collected under Cincinnati Children’s Hospital Medical Center (CCHMC) IRB approval.
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Trends in Cancer (2019)