Host Wnt5a potentiates microenvironmental regulation of ovarian cancer metastasis

Marwa Asem, Allison M. Young, Carlysa Oyama, Alejandro Claure De La Zerda, Yueying Liu, Jing Yang, Tyvette S. Hilliard, Jeffery Johnson, Elizabeth I. Harper, Ian Guldner, Siyuan Zhang, Toni Page-Mayberry, William J. Kaliney, M. Sharon Stack

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

The noncanonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden. Tumors formed in WNT5A knockout mice had elevated cytotoxic T cells, increased M1 macrophages, and decreased M2 macrophages, indicating that host Wnt5a promotes an immunosuppressive microenvironment. The Src family kinase Fgr was identified as a downstream effector of Wnt5a. These results highlight a previously unreported role for host-expressed Wnt5a in ovarian cancer metastasis and suggest Fgr as a novel target for inhibition of ovarian cancer metastatic progression. Significance: This study establishes host-derived Wnt5a, expressed by peritoneal mesothelial cells and adipocytes, as a primary regulator of ovarian cancer intraperitoneal metastatic dissemination and identifies Fgr kinase as novel target for inhibition of metastasis.

Original languageEnglish (US)
Pages (from-to)1156-1170
Number of pages15
JournalCancer research
Volume80
Issue number5
DOIs
StatePublished - Mar 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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