WNT5A inhibition alters the malignant peripheral nerve sheath tumor microenvironment and enhances tumor growth

Craig S. Thomson, Jay Pundavela, Melissa R. Perrino, Robert A. Coover, Kwangmin Choi, Katherine E. Chaney, Tilat A. Rizvi, David A. Largaespada, Nancy Ratner

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4229-4241
Number of pages13
JournalOncogene
Volume40
Issue number24
DOIs
StatePublished - Jun 17 2021

Bibliographical note

Funding Information:
Acknowledgements We thank the CCHMC research pathology core for tissue processing and embedding and the viral vector core for lentivirus preparation. This research was supported by the National Institute of Health (NIH) 5R01NS086219, to DAL and NR.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'WNT5A inhibition alters the malignant peripheral nerve sheath tumor microenvironment and enhances tumor growth'. Together they form a unique fingerprint.

Cite this