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

Abstract

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.

Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics

“…For example, osteosarcoma cells usually show high platelet activation inducing characteristics, which can induce platelet activation. Activated platelets secrete LPA and CLEC, which enhance the invasive ability of osteosarcoma through the LPA-LPAR1 axis and the interaction between platelet CLEC-2 and osteosarcoma podoplanin (37,38). And tumor cells can release soluble mediators such as ADP (16) to activate platelets and form polymers through TCIPA on the surface of tumor cells, so that platelets can wrap tumor cells, thus avoiding the attack of immune cells in the circulatory system (39).…”

Reduction of LPAR1 Expression in Neuroblastoma Promotes Tumor Cell Migration

“…Accumulated research has revealed the decreased expression of LPAR1 and its migration-inhibiting effects in tumors including prostate cancer, gastric cancer and pancreatic cancer, which is consistent with our results [ 7 , 12 , 13 ]. However, LPAR1 expression has also been reported to be significantly increased in other tumors, such as human hepatic cancer [ 29 ], osteosarcoma [ 30 ] and ovarian cancer [ 31 ], and to exert tumor-promoting effects directly or mediated by chemotherapy resistance [ 30 , 32 ]. The controversial research results about LPAR1 suggest its different signaling transduction pathways and functions in different types of tumor cells.…”

A Novel High-Throughput Screening Method for a Human Multicentric Osteosarcoma-Specific Antibody and Biomarker Using a Phage Display-Derived Monoclonal Antibody

“…It was found that when osteosarcoma cells come into contact with platelets in the bloodstream, platelets are activated, and the invasive potential is enhanced via LPA produced and released from the activated platelets, resulting in lung metastasis. This indicates that LPAR1 antagonist administration may inhibit pulmonary metastasis of osteosarcoma [ 44 ]. CAVIN1/PTRF, which is specifically expressed in HMOS as revealed in this study, should also be investigated with antagonists.…”