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

• Published in: Oncogene 2021-09, Vol.40 (36), p.5548-5558
• Main Authors: Takagi, Satoshi, Sasaki, Yuki, Koike, Sumie, Takemoto, Ai, Seto, Yosuke, Haraguchi, Mizuki, Ukaji, Takao, Kawaguchi, Tokuichi, Sugawara, Minoru, Saito, Masanori, Funauchi, Yuki, Ae, Keisuke, Matsumoto, Seiichi, Fujita, Naoya, Katayama, Ryohei
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/95; 14/5; 38/91; 42/41; 45/77; 631/67/1798; 631/67/322; 631/67/327; 64/60; Activation; Animal models; Animals; Apoptosis; Blood platelets; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood Platelets - pathology; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Bone Neoplasms - secondary; Care and treatment; Cell Biology; Cell Line, Tumor; Cell receptors; Development and progression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Invasiveness; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lysophosphatidic acid; Lysophospholipids - metabolism; Medical innovations; Medical prognosis; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Molecular modelling; Neoplasm Invasiveness; Neoplasm Metastasis; Oncology; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - pathology; Osteosarcoma cells; Phospholipids; Platelet Activation - drug effects; Platelets; Receptors, Lysophosphatidic Acid - antagonists & inhibitors; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - metabolism; Sarcoma; Therapeutic targets; Transcriptomes; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-01956-6

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.