Biological evidence of cancer stem-like cells and recurrent disease in osteosarcoma

Jubelin, Camille; Muñoz-García, Javier; Cochonneau, Denis; Moranton, Emilie; Heymann, Marie-Françoise; Heymann, Dominique

doi:10.20517/cdr.2021.130

Cited by 8 publications

(11 citation statements)

References 140 publications

(295 reference statements)

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“…Of note, in paediatric sarcomas, SOX2 was found to be the most associated with tumour initiation and growth, making cells with high expression of SOX2 the most fitting of the CSC phenotype 35 . SOX2 has also been implicated as essential for OS tumour growth and cell proliferation 36 . This is the first study to demonstrate that WNT5B regulates SOX2 expression in CSCs.…”

Section: Discussionmentioning

confidence: 76%

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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: Discussionmentioning

confidence: 76%

“… 35 SOX2 has also been implicated as essential for OS tumour growth and cell proliferation. 36 This is the first study to demonstrate that WNT5B regulates SOX2 expression in CSCs.…”

Section: Discussionmentioning

confidence: 86%

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

Perkins,

Murray,

Suthon

et al. 2024

Clinical & Translational Med

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“…Osteosarcoma develops under the pressure of random mutational changes, and its growth is led by preferential clonal proliferation and epigenetic modifications [54]. Understanding the pathogenesis of osteosarcoma is complicated by the low tumor incidence and significant genetic differences between subtypes.…”

Section: Coding Dna Changes In Osteosarcomamentioning

confidence: 99%

Cellular and Genetic Background of Osteosarcoma

Urlić

Jovičić

Ostojić

et al. 2023

CIMB

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Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach is limited due to high heterogeneity of tumors, and different underlying mutations. In this review, we will summarize new advances obtained by new technologies, such as next generation sequencing and single-cell sequencing. These new techniques have enabled better assessment of cell populations within osteosarcoma, as well as an understanding of the molecular pathogenesis. We also discuss the presence and properties of osteosarcoma stem cells—the cell population within the tumor that is responsible for metastasis, recurrence, and drug resistance.

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“…SOX2 inhibition may contribute to the effects of IOX-1 on OS cells SOX2 has been viewed as an oncogene in OS and knockdown of SOX2 can abrogate tumorigenicity 23 . To investigate the potential role of CSC in OS we inhibited CSC marker SOX2 using two short hairpin RNAs (shRNAs) in MG63-M10 and MG63-CR cells.…”

Section: Iox-1 Inhibits Stemness Properties Of Os Cellsmentioning

confidence: 99%

IOX-1 suppresses metastasis of osteosarcoma by upregulating histone H3 lysine trimethylation

Li¹,

Lee

Yang

et al. 2022

Preprint

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New therapeutic approaches are needed for metastatic osteosarcoma (OS), as survival rates remain low despite surgery and chemotherapy. Epigenetic changes, such as histone H3 methylation, play key roles in many cancers including OS, although the underlying mechanisms are not clear. In this study, human OS tissue and OS cell lines displayed lower levels of histone H3 lysine trimethylation compared with normal bone tissue and osteoblast cells. Treating OS cells with the histone lysine demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX-1) dose-dependently increased histone H3 methylation and inhibited cellular migratory and invasive capabilities, suppressed matrix metalloproteinase expression, reversed epithelial-to-mesenchymal transition by increasing levels of epithelial markers E-cadherin and ZO-1 and decreasing the expression of mesenchymal markers N-cadherin, vimentin, and TWIST, and also reduced stemness properties. An analysis of cultivated MG63 cisplatin-resistant (MG63-CR) cells revealed lower histone H3 lysine trimethylation levels compared with levels in MG63 cells. Exposing MG63-CR cells to IOX-1 increased histone H3 trimethylation and ATP-binding cassette transporter expression, potentially sensitizing MG63-CR cells to cisplatin. In conclusion, our study suggests that histone H3 lysine trimethylation is associated with metastatic OS and that IOX-1 or other epigenetic modulators present promising strategies to inhibit metastatic OS progression.

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Biological evidence of cancer stem-like cells and recurrent disease in osteosarcoma

Cited by 8 publications

References 140 publications

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

Cellular and Genetic Background of Osteosarcoma

IOX-1 suppresses metastasis of osteosarcoma by upregulating histone H3 lysine trimethylation

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