Elucidation of master regulators that determine the acquisition of metastatic phenotype in cancer cells and suppression of metastasis based on its control

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07243
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Keio University
• Principal Investigator: NOBUSUE HIROYUKI 慶應義塾大学, 医学部(信濃町), 特任助教 (90525685)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 細胞運動 / 転移 / アクチン細胞骨格 / 骨肉腫 / MKL1

Outline of Final Research Achievements

We transplanted subcutaneously malignant osteosarcoma cells (AXT cells) into syngeneic C57BL/6 mice and then analyzed the expression of megakaryoblastic leukemia 1 (MKL1), which is a transcriptional regulator, in primary tumors and metastatic tumors to the lung. We found that AXT cells in primary tumors did not express MKL1, whereas AXT cells in metastatic tumors to the lung highly expressed MKL1 in the nucleus. Induction of MKL1 in AXT cells resulted in a significant increase of the invasion capability and the sphere-forming activity. In addition, GSEA of the microarray data revealed that induction of MKL1 enriches gene sets associated with invasion and metastasis, such as epithelial-mesenchymal transition (EMT) and Notch signaling. These findings thus suggest that MKL1 acts as a critical factor that controls the acquisition of metastatic phenotype in osteosarcoma cells.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、アクチン細胞骨格の動態によって直接制御されるMKL1を分子標的として制御することで、これまでアプローチが困難であった転写制御シグナルを変化させ、がん細胞の転移能獲得を阻害し転移抑制するという先駆的治療法の開発の可能性を見出しており、学術的に新しい概念を生み出すだけでなく、社会的意義も極めて大きい。