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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 char...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429042/
https://www.ncbi.nlm.nih.gov/pubmed/34302117
http://dx.doi.org/10.1038/s41388-021-01956-6
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author 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
author_facet 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
author_sort Takagi, Satoshi
collection PubMed
description 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.
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spelling pubmed-84290422021-09-29 Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis 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 Oncogene Article 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. Nature Publishing Group UK 2021-07-23 2021 /pmc/articles/PMC8429042/ /pubmed/34302117 http://dx.doi.org/10.1038/s41388-021-01956-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis
title Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis
title_full Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis
title_fullStr Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis
title_full_unstemmed Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis
title_short Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis
title_sort platelet-derived lysophosphatidic acid mediated lpar1 activation as a therapeutic target for osteosarcoma metastasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429042/
https://www.ncbi.nlm.nih.gov/pubmed/34302117
http://dx.doi.org/10.1038/s41388-021-01956-6
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