Malignant peripheral nerve sheath tumors (
MPNST) are aggressive
soft-tissue sarcomas that cause significant mortality in adults with
neurofibromatosis type 1. We compared gene expression of
growth factors in normal human nerves to
MPNST and normal human Schwann cells to
MPNST cell lines. We identified WNT5A as the most significantly upregulated
ligand-coding gene and verified its
protein expression in
MPNST cell lines and
tumors. In many contexts WNT5A acts as an oncogene. However, inhibiting WNT5A expression using
shRNA did not alter
MPNST cell proliferation, invasion, migration, or survival in vitro. Rather, shWNT5A-treated
MPNST cells upregulated mRNAs associated with the remodeling of extracellular matrix and with immune cell communication. In addition, these cells secreted increased amounts of the proinflammatory
cytokines CXCL1, CCL2,
IL6, CXCL8, and ICAM1. Versus controls, shWNT5A-expressing
MPNST cells formed larger
tumors in vivo. Grafted
tumors contained elevated macrophage/stromal cells, larger and more numerous blood vessels, and increased levels of Mmp9, Cxcl13, Lipocalin-1, and Ccl12. In some
MPNST settings, these effects were mimicked by targeting the WNT5A receptor ROR2. These data suggest that the non-canonical Wnt
ligand WNT5A inhibits
MPNST tumor formation by modulating the
MPNST microenvironment, so that blocking WNT5A accelerates
tumor growth in vivo.