Osteoclast-induced modulation of osteosarcoma migration: Exploring the role of CSF3/STAT3/MMP9
Conference item
Paternina Martinez, D., Roberts. S.J. and Roberts, H.C. 2024. Osteoclast-induced modulation of osteosarcoma migration: Exploring the role of CSF3/STAT3/MMP9. Bone Research Society Annual Meeting 2024. Shefield, UK 10 - 12 Jul 2024
| Title | Osteoclast-induced modulation of osteosarcoma migration: Exploring the role of CSF3/STAT3/MMP9 |
|---|---|
| Authors | Paternina Martinez, D., Roberts. S.J. and Roberts, H.C. |
| Abstract | Metastatic disease significantly impacts the prognosis of osteosarcoma (OS) patients, with survival rates ranging from 20% to 30% for metastatic disease compared to up to 80% for nonmetastatic. Unfortunately, this figure has plateaued over the past few decades, partly due to a paucity of research into mediators of the metastatic process. Recent evidence shows that targeting osteoclasts (OCs) with zoledronic acid (ZA) increases the number of metastatic lung lesions clinically, whereas treatment with fulvestran increases OC numbers and decreases metastatic lesions. This links OC function to OS metastasis. Through an in vitro model of OS metastasis, we have found that the highly metastatic OS cell line 143B contains a subset of highly migratory spheroids with enhanced expression of stemness and metastasis associated genes Oct3/4 (10-fold (p≤0.001)), Nanog (4-fold; p≤0.001), Sox2 (6-fold; p≤0.001), and CXCR4 (2-fold; p≤0.001) compared to monolayer cells. We have termed these spheroids with enhanced migratory capabilities ‘Migratory Bodies’ (MBs). We subsequently assessed the effect of OC-released factors on MB formation, where a significant reduction in MB formation in 143B cells cultured with OC-conditioned media compared to control (43%; p≤0.001) or conditioned media from OCs treated with ZA (OC-ZA, 33%, p≤0.001) was observed. Furthermore, 143B cells cultured with OC-conditioned media or OC-ZA-conditioned media exhibited divergent gene expression as assessed by RNA-sequencing. Differentially expressed genes were validated by RT-qPCR; MMP9 (2.4-fold decrease; p≤0.001), MMP14 (2-fold decrease; p≤0.01), CSF3 (2.5fold decrease; p≤0.01) and SPOCK (1.6-fold decrease; p≤0.01). In an attempt to mimic OC-conditioned media, chemical inhibitors of MMP9 and STAT3 (downstream of CSF3) were tested in the MB metastasis assay. Both STAT3 and MMP9 expression is linked to lower survival in OS patients using the R2: Genomics Analysis and Visualization Platform. Inhibition of STAT3 and MMP9 significantly reduced MB formation from 143B cells by 76% and 31% (p≤0.001) respectively, compared to control. Collectively, these data indicate that OCs release factors that repress MB formation in highly metastatic 143B cells. This supports our hypothesis that OS may reside in the bone environment due to interaction with bone cells. Contrary to Paget’s “seed and soil” hypothesis, it appears that disruption of this interaction leads to increased incidence of pulmonary metastasis . Lastly, our data suggests a novel approach to combat highly metastatic and migratory osteosarcoma cells by targeting STAT3 and/or MMP9. |
| Sustainable Development Goals | 3 Good health and well-being |
| Middlesex University Theme | Health & Wellbeing |
| Conference | Bone Research Society Annual Meeting 2024 |
| Publication process dates | |
| Completed | 10 Jul 2024 |
| Deposited | 10 Oct 2025 |
| Output status | Published |
| Additional information | The abstract for this oral presentation was published in the journal JBMR Plus: |
| Related Output | |
| Is documented by | https://doi.org/10.1093/jbmrpl/ziae109 |
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