Elucidation of scaffold-dependent pulmonary growth mechanisms in osteosarcoma and their application to therapy for inhibiting pulmonary metastasis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09290
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: 医療法人徳洲会野崎徳洲会病院(附属研究所)
• Principal Investigator: Yui Yoshihiro 医療法人徳洲会野崎徳洲会病院(附属研究所), 研究所, 主任研究員 (20547757)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 骨肉腫 / 肺転移

Outline of Final Research Achievements

The 5-year survival rate of osteosarcoma has not shown significant improvement over the past 30 years, and the establishment of novel therapeutic strategies to suppress pulmonary metastasis, the primary cause of mortality, is desired. In this study, we attempted to elucidate scaffold-dependent, mechanically insensitive growth mechanisms of osteosarcoma cells in environments poor in collagen fibers, where they serve as soft scaffolds, using in vivo CRISPR activation screening and in vitro RNA-seq analysis. RNA-seq analysis revealed increased expression of multiple Cdc42GEFs and decreased expression of multiple Cdc42GAPs in highly metastatic LM8 cells. Furthermore, it was found that ribosome activity is enhanced in soft environments. CRISPR activation screening also confirmed amplification of ribosome-related gene clusters in metastatic osteosarcoma cells.

Free Research Field

腫瘍の転移

Academic Significance and Societal Importance of the Research Achievements

本研究は、骨肉腫の肺転移メカニズムに対する工学的な新規のアプローチである。この研究によりリボソーム活性やCdc42活性が、“足場の乏しい軟らかい環境”での骨肉腫細胞の増殖を促進し、肺転移を増加させるメカニズムを明らかになれば、肺組織の軟らかさに対応した増殖メカニズムという新たな治療標的を発見し、骨肉腫肺転移の抑制療法を開発することができる。