WNT5B in cellular signaling pathways

Perkins, Rachel S.; Suthon, Sarocha; Miranda-Carboni, Gustavo A.; Krum, Susan A.

doi:10.1016/j.semcdb.2021.09.019

Cited by 13 publications

(7 citation statements)

References 73 publications

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“…To elucidate the mechanism of WNT5B regulation of SOX2 , we analysed the expression of downstream targets of WNT5B. 25 In pancreatic CSCs, NFATc1 was shown to upregulate SOX2 expression and then combined with SOX2 as a binding partner to regulate the transcription of epithelial to mesenchymal transition markers and stemness genes. 26 KO of WNT5B led to the reduced protein levels of NFATc1 and this could be rescued by the addition of rWNT5B (Figure 4G,H ).…”

Section: Resultsmentioning

confidence: 99%

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WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

Perkins,

Murray,

Suthon

et al. 2024

Clinical & Translational Med

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BackgroundTreatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival.MethodsUsing tumor‐spheroids to model cancer stem‐like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem‐like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target.ResultsIn osteosarcoma cell lines and patient‐derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere‐forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient‐derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression.ConclusionsTogether, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients.Key points WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

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Section: Resultsmentioning

confidence: 99%

“…One of the receptor tyrosine kinases through which WNT5B can signal, 25 ROR1, has gained increasing attention in the field of therapeutic targets. ROR1 has been implicated in cancers such as leukaemia, breast cancer and ovarian cancer as a regulator of tumour cell survival, drug resistance, stemness, and proliferation 40 .…”

Section: Discussionmentioning

confidence: 99%

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

Perkins,

Murray,

Suthon

et al. 2024

Clinical & Translational Med

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“…This finding may be due to Wnt5b different interacting via crosstalk with the Wnt/β-catenin pathway downstream of the receptor, but where and how this interaction occurs in the 2 different groups should be illustrated later. 43 Further study is needed to investigate these downstream signalling pathways and how they regulate inflammatory and odontogenic genes in odontoblasts.…”

Section: Discussionmentioning

confidence: 99%

Piezo Mediates the Mechanosensation and Injury-Repair of Pulpo-Dentinal Complex

Xu,

Guo,

Liu

et al. 2024

International Dental Journal

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“…WNT5B, a member of the WNT family proteins, has been described as an inducer of the noncanonical, beta-catenin independent WNT signaling pathways and is often considered as an antagonist of the canonical WNT signaling. It has been reported to regulate cell migration, proliferation, and differentiation during development (32). WNT5B is upregulated in triple negative breast cancer patient samples and correlates with a worse prognosis (15).…”

Section: Discussionmentioning

confidence: 99%

DLL4-Notch3-WNT5B axis is a novel mediator of bi-directional pro-metastatic crosstalk between melanoma and lymphatic endothelial cells

Alve¹,

Gramolelli

Jukonen³

et al. 2023

Preprint

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Despite strong indications that melanoma interaction with lymphatic vessels actively promotes melanoma progression, the molecular mechanisms are not yet completely understood. To characterize molecular factors of this crosstalk we established human primary lymphatic endothelial cell (LEC) co-cultures with human melanoma cell lines. Here, we show that co-culture with melanoma cells induced transcriptomic changes in LECs and led to multiple alterations in their function. WNT5B, a paracrine signaling molecule upregulated in melanoma cells upon LEC interaction, was found contributing to the functional changes in LECs. Moreover, WNT5B transcription was regulated by Notch3 in melanoma cells following the co-culture with LECs, and Notch3 and WNT5B were co-expressed in melanoma patient primary tumor and metastasis samples. Moreover, melanoma cells derived from LEC co-culture escaped efficiently from the primary site to the proximal tumor draining lymph nodes, which was impaired upon WNT5B depletion. This supports the role of WNT5B in promoting the metastatic potential of melanoma cells through its effects on LECs. Finally, DLL4, a Notch ligand expressed in LECs, was identified as an upstream inducer of the Notch3-WNT5B axis in melanoma. This study elucidates WNT5B as a novel molecular factor mediating bi-directional crosstalk between melanoma cells and lymphatic endothelium and promoting melanoma metastasis.

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WNT5B in cellular signaling pathways

Cited by 13 publications

References 73 publications

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

Piezo Mediates the Mechanosensation and Injury-Repair of Pulpo-Dentinal Complex

DLL4-Notch3-WNT5B axis is a novel mediator of bi-directional pro-metastatic crosstalk between melanoma and lymphatic endothelial cells

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