Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis

Osteosarcoma is the most common primary malignant bone cancer, with high rates of pulmonary metastasis. Osteosarcoma patients with pulmonary metastasis have worse prognosis than those with localized disease, leading to dramatically reduced survival rates. Therefore, understanding the biological characteristics of metastatic osteosarcoma and the molecular mechanisms of invasion and metastasis of osteosarcoma cells will lead to the development of innovative therapeutic intervention for advanced osteosarcoma. Here, we identified that osteosarcoma cells commonly exhibit high platelet activation-inducing characteristics, and molecules released from activated platelets promote the invasiveness of osteosarcoma cells. Given that heat-denatured platelet releasate maintained the ability to promote osteosarcoma invasion, we focused on heat-tolerant molecules, such as lipid mediators in the platelet releasate. Osteosarcoma-induced platelet activation leads to abundant lysophosphatidic acid (LPA) release. Exposure to LPA or platelet releasate induced morphological changes and increased invasiveness of osteosarcoma cells. By analyzing publicly available transcriptome datasets and our in-house osteosarcoma patient-derived xenograft tumors, we found that LPA receptor 1 (LPAR1) is notably upregulated in osteosarcoma. LPAR1 gene KO in osteosarcoma cells abolished the platelet-mediated osteosarcoma invasion in vitro and the formation of early pulmonary metastatic foci in experimental pulmonary metastasis models. Of note, the pharmacological inhibition of LPAR1 by the orally available LPAR1 antagonist, ONO-7300243, prevented pulmonary metastasis of osteosarcoma in the mouse models. These results indicate that the LPA-LPAR1 axis is essential for the osteosarcoma invasion and metastasis, and targeting LPAR1 would be a promising therapeutic intervention for advanced osteosarcoma.

 

Comment:

Thank you for providing this information on the role of the LPA-LPAR1 axis in osteosarcoma invasion and metastasis. It appears that osteosarcoma cells exhibit high platelet activation-inducing characteristics, and molecules released from activated platelets, such as lysophosphatidic acid (LPA), promote the invasiveness of these cancer cells.

Your study found that LPA receptor 1 (LPAR1) is notably upregulated in osteosarcoma, and its knockout in osteosarcoma cells abolished platelet-mediated invasion in vitro and the formation of early pulmonary metastatic foci in experimental models of pulmonary metastasis. Additionally, the pharmacological inhibition of LPAR1 using the LPAR1 antagonist ONO-7300243 prevented pulmonary metastasis in mouse models.

These findings suggest that targeting LPAR1 could be a promising therapeutic intervention for advanced osteosarcoma, as it plays a crucial role in the invasion and metastasis of the disease. By inhibiting LPAR1, the spread of osteosarcoma to the lungs could potentially be prevented or reduced, improving patient prognosis and survival rates.

It's important to note that the information you provided is based on a hypothetical scenario or research study description. While targeting LPAR1 shows promise in preclinical models, further research and clinical trials would be necessary to validate its efficacy and safety as a therapeutic intervention for advanced osteosarcoma in humans.