TY - JOUR
T1 - Host Wnt5a potentiates microenvironmental regulation of ovarian cancer metastasis
AU - Asem, Marwa
AU - Young, Allison M.
AU - Oyama, Carlysa
AU - De La Zerda, Alejandro Claure
AU - Liu, Yueying
AU - Yang, Jing
AU - Hilliard, Tyvette S.
AU - Johnson, Jeffery
AU - Harper, Elizabeth I.
AU - Guldner, Ian
AU - Zhang, Siyuan
AU - Page-Mayberry, Toni
AU - Kaliney, William J.
AU - Stack, M. Sharon
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-1601
DO - 10.1158/0008-5472.CAN-19-1601
M3 - Article
C2 - 31932454
AN - SCOPUS:85081132404
SN - 0008-5472
VL - 80
SP - 1156
EP - 1170
JO - Cancer research
JF - Cancer research
IS - 5
ER -