Steering human osteosarcoma cells to a more differentiated state

Full project title: Steering human osteosarcoma cells to a more differentiated state

Duration: Ongoing

Project lead for CBR: Dr Jason Peter Mansell

Other UWE Bristol researcher: Dr Alexander Greenhough

Osteosarcoma (OS), which primarily affects children and adolescents, is a highly aggressive mesenchymal malignancy, with metastases typically spreading to the lungs. Diagnosis of metastatic disease equates to a bleak prognosis, with five-year survival rates largely unchanged for nearly half a century.  

In recent years, we have been working at promoting OS cell maturation. Transitioning proliferative immature OS cells to a more differentiated state is likely to reduce their aggressive nature and may make them more amenable to chemo/radiotherapy. Our model of differentiation consists of co-stimulating OS cells with the less calcaemic vitamin D analogue, EB1089, and the pleiotropic lipid growth factor, lysophosphatidic acid (LPA). This growth factor has relevance to both bone and cancer; kidney-derived glycerol-3-phosphate is converted to LPA within the bone compartment where it stimulates the synthesis of FGF23, a key mediator of phosphate homeostasis.

Furthermore, LPA is a product of platelet activation and cancer cells can directly activate platelets by secreting thrombin and adenosine 5’-diphosphate. Signalling co-operation between LPA and EB1089 results in a synergistic increase in alkaline phosphatase (ALP) expression, a marker of more mature or differentiated cells. However, under hypoxic conditions, the pro-differentiating ability of LPA/EB1089 is markedly attenuated. 

We are therefore seeking ways of restoring the ability of LPA/EB1089 to enhance OS cell maturation under hypoxic conditions.  

• Stephens E, Greenhough A, Mansell JP. The Nrf2 inhibitor Brusatol promotes human osteosarcoma (MG63) growth and blocks EB1089-induced differentiation. Int. J. Mol. Sci 2025, 3;26(19):9675. doi: 10.3390/ijms26199675. 
• Evans H, Greenhough A, Perry L, Lasanta G, Gonzalez CM, Mourino A, Mansell JP. Hypoxia Compromises the Differentiation of Human Osteosarcoma Cells to CAR-R, a Hydroxylated Derivative of Lithocholic Acid and Potent Agonist of the Vitamin D Receptor. Int. J. Mol. Sci 2025, 26, 365. https://doi.org/ 10.3390/ijms26010365. 
• Elkodous MA, Elkhenany H, Mansell JP. Comparison of Mxene and SWCNTs effectiveness for osteoblast differentiation: A preliminary study with MG-63 cells. NANO: Brief Reports and Reviews 2024, 19: 1-9.  
• Elkhenany H, Elkodous MA, Mansell JP. Ternary nanocomposite potentiates the lysophosphatidic acid effect on human osteoblast (MG63) maturation. Nanomedicine 2023, doi: 10.2217/nnm-2023-0117.  
• Mansell JP, Tanatani A, Kagechika H. An N-Cyanoamide Derivative of Lithocholic Acid Co-Operates with Lysophosphatidic Acid to Promote Human Osteoblast (MG63) Differentiation. Biomolecules 2023, 13: 1113.   

For further information about the project, please contact Dr Jason P Mansell (jason.mansell@uwe.ac.uk).