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

Oncogene volume 40, pages 4229–4241 (2021)Cite this article

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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.

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Fig. 1: Growth factors, specifically WNT5A, are differentially expressed in NF1-associated disease cells and tissues.
Fig. 2: shWNT5A-treated MPNST cell lines grow larger in vivo.
Fig. 3: Knockdown of WNT5A results in upregulated factors associated with the microenvironment.
Fig. 4: shWNT5A-treated MPNST cell lines show enhanced secretion of cytokines.
Fig. 5: Grafted tumors show enhanced presence of host cells.
Fig. 6: Cytokine analysis in the shWNT5A environment shows increased Ccl12, Cxcl13, Mmp9, and Lipocalin-2.

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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.

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  1. Robert A. Coover

    Present address: Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, NC, USA

Authors and Affiliations

  1. Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Craig S. Thomson

  2. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

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

  3. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Melissa R. Perrino & Nancy Ratner

  4. Department of Genetics, Cell Biology, and Development, College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA

    David A. Largaespada

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Contributions

CST carried out in vitro studies, data analysis, statistical analyses, and drafted the manuscript. JP and RAC contributed to data analysis; JP drew Fig. 6C. MP and TAR carried out histological analyses of tumor tissues. KEC and CST conducted xenografts. KC analyzed microarray and RNA-sequencing data. NR proposed and oversaw the project. Financial support was to NR and DAL. All the authors reviewed the manuscript.

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Correspondence to Nancy Ratner.

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Conflict of interest

Revolution Medicine and Boehringer Ingelheim fund some of NR’s research, unrelated to this manuscript. DAL is the co-founder and co-owner of biotechnology companies including NeoClone Biotechnologies, Inc., Discovery Genomics, Inc. (recently acquired by Immunsoft, Inc.), B-MoGen Biotechnologies, Inc. (recently acquired by the BioTechne Corporation), and Luminary Therapeutics, Inc. He consults for Genentech, Inc., which funds some of his research and holds equity in and serves as the Chief Scientific Officer of Surrogen, a subsidiary of Recombinetics, a genome-editing company. The business of these companies is unrelated to this manuscript.

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Thomson, C.S., Pundavela, J., Perrino, M.R. et al. WNT5A inhibition alters the malignant peripheral nerve sheath tumor microenvironment and enhances tumor growth. Oncogene 40, 4229–4241 (2021). https://doi.org/10.1038/s41388-021-01773-x

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