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Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates
Maya Kansara1, Michael Tsang, Laurent Kodjabachian
1Ian Potter Foundation Centre for Cancer Genetics and Preventative Medicine, and Sir Donald and Lady Trescowthick Laboratories, Peter MacCallumCancer Centre, Melbourne, Victoria, Australia.
Abstract:
Wnt signaling increases bone mass by stimulating osteoblast lineage commitment and expansion and forms the basis for novel anabolic therapeutic strategies being developed for osteoporosis. These strategies include derepression of Wnt signaling by targeting secreted Wnt pathway antagonists, such as sclerostin. However, such therapies are associated with safety concerns regarding an increased risk of osteosarcoma, the most common primary malignancy of bone. Here, we analyzed 5 human osteosarcoma cell lines in a high-throughput screen for epigenetically silenced tumor suppressor genes and identified Wnt inhibitory factor 1 (WIF1), which encodes an endogenous secreted Wnt pathway antagonist, as a candidate tumor suppressor gene. In vitro, WIF1 suppressed beta-catenin levels in human osteosarcoma cell lines, induced differentiation of human and mouse primary osteoblasts, and suppressed the growth of mouse and human osteosarcoma cell lines. Wif1 was highly expressed in the developing and mature mouse skeleton, and, although it was dispensable for normal development, targeted deletion of mouse Wif1 accelerated development of radiation-induced osteosarcomas in vivo. In primary human osteosarcomas, silencing of WIF1 by promoter hypermethylation was associated with loss of differentiation, increased beta-catenin levels, and increased proliferation. These data lead us to suggest that derepression of Wnt signaling by targeting secreted Wnt antagonists in osteoblasts may increase susceptibility to osteosarcoma.
Insights
Wnt inhibitory factor 1 (WIF1) acts as a tumor suppressor in bone by inhibiting Wnt signaling. Silencing WIF1 in osteosarcomas promotes tumor growth and may increase cancer risk when Wnt signaling is therapeutically activated.
Area of Science:
- Bone biology and oncology
- Molecular mechanisms of cancer development
Background:
- Wnt signaling is crucial for bone mass regulation and a target for osteoporosis therapies.
- Therapeutic Wnt activation carries a risk of osteosarcoma, the primary bone malignancy.
Purpose of the Study:
- To identify tumor suppressor genes epigenetically silenced in osteosarcoma.
- To investigate the role of Wnt inhibitory factor 1 (WIF1) as a potential tumor suppressor in bone.
Main Methods:
- High-throughput screening of human osteosarcoma cell lines for silenced tumor suppressor genes.
- In vitro assays assessing WIF1's effects on beta-catenin, osteoblast differentiation, and osteosarcoma cell growth.
- In vivo studies using mouse models to evaluate Wif1's role in radiation-induced osteosarcoma development.
- Analysis of WIF1 promoter methylation in human osteosarcomas.
Main Results:
- WIF1 was identified as a candidate tumor suppressor gene epigenetically silenced in osteosarcoma.
- In vitro, WIF1 suppressed beta-catenin, induced osteoblast differentiation, and inhibited osteosarcoma cell growth.
- Wif1 deletion accelerated radiation-induced osteosarcoma in mice.
- WIF1 silencing via promoter hypermethylation correlated with dedifferentiation, increased beta-catenin, and proliferation in human osteosarcomas.
Conclusions:
- WIF1 functions as a tumor suppressor in the bone microenvironment.
- Therapeutic strategies that derepress Wnt signaling by inhibiting antagonists like sclerostin may increase osteosarcoma susceptibility due to WIF1 silencing.
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