Host Wnt5a Potentiates Microenvironmental Regulation of Ovarian Cancer Metastasis

Overview

Journal Cancer Res

Specialty Oncology

Date 2020 Jan 15

PMID 31932454

Citations 32

Authors

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

Affiliations

Soon will be listed here.

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 significantly reduced peritoneal metastatic tumor burden. Tumors formed in 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. 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.

Citing Articles

Basal cell adhesion molecule (BCAM) promotes mesothelial-to-mesenchymal transition and tumor angiogenesis through paracrine signaling.

Sivakumar S, Lieber S, Dietze R, Beutgen V, Sutor E, Heidemann S Cell Commun Signal. 2025; 23(1):136.

PMID: 40082910 PMC: 11907816. DOI: 10.1186/s12964-025-02128-9.

Single-cell and spatial transcriptomic profiling revealed niche interactions sustaining growth of endometriotic lesions.

Liu S, Li X, Gu Z, Wu J, Jia S, Shi J Cell Genom. 2025; 5(1):100737.

PMID: 39788102 PMC: 11770218. DOI: 10.1016/j.xgen.2024.100737.

Construction of a novel lipid drop-mitochondria-associated genetic profile for predicting the survival and prognosis of lung adenocarcinoma.

Cai R, Lin H, Cheng Q, Mao Q, Zhang C, Tan Y Discov Oncol. 2024; 15(1):668.

PMID: 39551861 PMC: 11570572. DOI: 10.1007/s12672-024-01526-8.

Emerging roles and biomarker potential of WNT6 in human cancers.

Ferreira J, Goncalves C, Costa B Cell Commun Signal. 2024; 22(1):538.

PMID: 39529066 PMC: 11552340. DOI: 10.1186/s12964-024-01892-4.

Macrophage diversity in cancer dissemination and metastasis.

Mantovani A, Marchesi F, Di Mitri D, Garlanda C Cell Mol Immunol. 2024; 21(11):1201-1214.

PMID: 39402303 PMC: 11528009. DOI: 10.1038/s41423-024-01216-z.

References

Fuster J, Zuriaga M, Ngo D, Farb M, Aprahamian T, Yamaguchi T . Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes. 2014; 64(4):1235-48. PMC: 4375084. DOI: 10.2337/db14-1164. View

Catalan V, Gomez-Ambrosi J, Rodriguez A, Perez-Hernandez A, Gurbindo J, Ramirez B . Activation of noncanonical Wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation. J Clin Endocrinol Metab. 2014; 99(8):E1407-17. DOI: 10.1210/jc.2014-1191. View

Preston C, Maurer M, Oberg A, Visscher D, Kalli K, Hartmann L . The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T cells correlate with poor clinical outcome in human serous ovarian cancer. PLoS One. 2013; 8(11):e80063. PMC: 3828213. DOI: 10.1371/journal.pone.0080063. View

Barbolina M, Burkhalter R, Stack M . Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment. Biochem J. 2011; 437(1):1-12. PMC: 3133882. DOI: 10.1042/BJ20110112. View

McNeish I, Ledermann J, Webber L, James L, Kaye S, Hall M . A randomised, placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer†. Ann Oncol. 2014; 25(10):1988-1995. DOI: 10.1093/annonc/mdu363. View

Pashirzad M, Shafiee M, Rahmani F, Behnam-Rassouli R, Hoseinkhani F, Ryzhikov M . Role of Wnt5a in the Pathogenesis of Inflammatory Diseases. J Cell Physiol. 2016; 232(7):1611-1616. DOI: 10.1002/jcp.25687. View

Naora H, Montell D . Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer. 2005; 5(5):355-66. DOI: 10.1038/nrc1611. View

Coffman L, Burgos-Ojeda D, Wu R, Cho K, Bai S, Buckanovich R . New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination. Transl Res. 2016; 175:92-102.e2. PMC: 5003680. DOI: 10.1016/j.trsl.2016.03.016. View

Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M . Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 2009; 125(6):1276-84. DOI: 10.1002/ijc.24378. View

10.

Mojic M, Takeda K, Hayakawa Y . The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion. Int J Mol Sci. 2017; 19(1). PMC: 5796039. DOI: 10.3390/ijms19010089. View

11.

Ghosh M, Collins G, Vandanmagsar B, Patel K, Brill M, Carter A . Activation of Wnt5A signaling is required for CXC chemokine ligand 12-mediated T-cell migration. Blood. 2009; 114(7):1366-73. PMC: 2727408. DOI: 10.1182/blood-2008-08-175869. View

12.

Sen B, Johnson F . Regulation of SRC family kinases in human cancers. J Signal Transduct. 2011; 2011:865819. PMC: 3135246. DOI: 10.1155/2011/865819. View

13.

Roby K, TAYLOR C, Sweetwood J, Cheng Y, Pace J, Tawfik O . Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis. 2000; 21(4):585-91. DOI: 10.1093/carcin/21.4.585. View

14.

Zhao C, Bu X, Wang W, Ma T, Ma H . GEC-derived SFRP5 inhibits Wnt5a-induced macrophage chemotaxis and activation. PLoS One. 2014; 9(1):e85058. PMC: 3885681. DOI: 10.1371/journal.pone.0085058. View

15.

Jin Z, Zhao C, Han X, Han Y . Wnt5a promotes ewing sarcoma cell migration through upregulating CXCR4 expression. BMC Cancer. 2012; 12:480. PMC: 3517772. DOI: 10.1186/1471-2407-12-480. View

16.

Rauner M, Stein N, Winzer M, Goettsch C, Zwerina J, Schett G . WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J Bone Miner Res. 2011; 27(3):575-85. DOI: 10.1002/jbmr.1488. View

17.

Pradeep S, Kim S, Wu S, Nishimura M, Chaluvally-Raghavan P, Miyake T . Hematogenous metastasis of ovarian cancer: rethinking mode of spread. Cancer Cell. 2014; 26(1):77-91. PMC: 4100212. DOI: 10.1016/j.ccr.2014.05.002. View

18.

Torre L, Trabert B, DeSantis C, Miller K, Samimi G, Runowicz C . Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018; 68(4):284-296. PMC: 6621554. DOI: 10.3322/caac.21456. View

19.

Loughran E, Leonard A, Hilliard T, Phan R, Yemc M, Harper E . Aging Increases Susceptibility to Ovarian Cancer Metastasis in Murine Allograft Models and Alters Immune Composition of Peritoneal Adipose Tissue. Neoplasia. 2018; 20(6):621-631. PMC: 5994778. DOI: 10.1016/j.neo.2018.03.007. View

20.

Asem M, Buechler S, Wates R, Miller D, Stack M . Wnt5a Signaling in Cancer. Cancers (Basel). 2016; 8(9). PMC: 5040981. DOI: 10.3390/cancers8090079. View