Silencing ROR1 and ROR2 Inhibits Invasion and Adhesion in an Organotypic Model of Ovarian Cancer Metastasis
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// Claire Henry 1 , Neville Hacker 2 and Caroline Ford 1 1 Gynaecological Cancer Research Group, Lowy Cancer Research Centre and School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, Australia 2 Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, Australia Correspondence to: Caroline Ford, email: caroline.ford@unsw.edu.au Keywords: ROR2; ROR1; epithelial ovarian cancer; omentum; metastasis Received: August 29, 2017 Accepted: October 27, 2017 Published: November 20, 2017 ABSTRACT OBJECTIVE: Elevated expression of the ROR1 and ROR2 Wnt receptors has been noted in both the tumour and stromal compartments of ovarian cancer patient tissue samples. In vitro studies have suggested these receptors play a role in ovarian cancer metastasis. However, these previous studies have utilised simple 2D in vitro models to investigate cancer cell growth and migration, which does not allow investigation of stromal involvement in Wnt driven metastasis. AIM: To investigate targeting ROR1 and ROR2 using a primary co-culture 3D model of epithelial ovarian cancer dissemination to the omentum. METHODS: Primary fibroblasts (NOF) and mesothelial (HPMC) cells were isolated from fresh samples of omentum collected from women with benign or non-metastatic conditions and cultured with collagen to produce a organotypic 3D model. Stable shRNA knockdown of ROR1, ROR2 and double ROR1/ROR2 in OVCAR4 cells were plated onto the 3D model to measure adhesion, or using a transwell to measure invasion. Gene expression changes in primary cells upon OVCAR4 interaction was evaluated using indirect transwell co-culture. RESULTS: Double knockdown of ROR1 and ROR2 strongly inhibited cell adhesion (p<0.05) and invasion (P<0.05) to the omentum model. ROR2 was up regulated in primary fibroblasts when cultured with OVCAR4 (P=0.05) and ectopic overexpression of ROR2 in NOFs inhibited cell proliferation (P<0.01) but increased cell migration. CONCLUSION: The combination of ROR1 and ROR2 signalling influences ovarian cancer dissemination to the omentum, however ROR2 may also play a role in stromal activation during metastasis. Therefore, targeting both ROR1 and ROR2 may be a powerful approach to treating ovarian cancer.
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Henry and colleagues described dynamic roles of the receptor tyrosine kinases ROR1 and ROR2 in different omental cell types that promote cancer cell adhesion in early metastasis.
“Further, Henry and colleagues described the dynamic roles of the receptor tyrosine kinases ROR1 and ROR2 in different omental cell types that promote cancer cell adhesion in early metastasis (Henry et al., 2017).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Henry et al., 2017
Three-dimensional co-culture systems of ovarian cancers and mesothelial cells, including the organotypic omental mesothelium model, have enabled the study of mechanisms driving peritoneal and omental metastasis.
“Three-dimensional co-culture systems of ovarian cancers and mesothelial cells, including the organotypic omental mesothelium model (described in Section 5.2.4) have also enabled the study of mechanisms driving peritoneal and omental metastasis (Iwanicki et al., 2011; Henry et al., 2017; Shishido et al., 2018; Loessner et al., 2019).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Henry et al., 2017
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References 39 · Cited by 37
- Authors
- Henry, C., Hacker, N., & Ford, C.
- Affiliations
- UNSW Sydney (AU)
- Royal Hospital for Women (AU)
- Corresponding author
- Ford, Caroline
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2017-11-20
- Volume
- 8
- Issue
- 68
- Pages
- 112727-112738
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5762545
- OpenAlex
- W2770576214
- Cited by
- 37
- References
- 39
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 6 · 2019: 3 · 2018: 5
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ovarian Cancer Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- ROR1, ROR2, Wnt receptors, epithelial ovarian cancer, omental metastasis, tumor invasion, cell adhesion, mesothelial cells, fibroblasts, shRNA knockdown, tumor stroma, metastasis suppression, cell migration, cell proliferation
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