Elucidation of the Mechanisms Governing the Proliferation, Migration and Metastasis of Oral Cancer Cells using Single Cell Analysis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03851
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Watabe Tetsuro 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (00334235)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 口腔がん / 増殖 / 運動 / 転移 / シングルセル解析 / TGF-β

Outline of Final Research Achievements

TGF-β increases epithelial cancer cell migration and metastasis by inducing EMT. TGF-β also inhibits cell proliferation by inducing G1 phase cell-cycle arrest. However, the correlation between these tumor-promoting and -suppressing effects remains unclear. Here, we show that TGF-β confers higher motility and metastatic ability to oral cancer cells in G1 phase. Mechanistically, KRTAP2-3 is a regulator of these dual effects of TGF-β, and its expression is correlated with tumor progression in patients with head and neck cancer and migratory and metastatic potentials of oral cancer cells. Furthermore, scRNA seq reveals that TGF-β generates two populations of mesenchymal cancer cells with differential cell-cycle status through two distinctive EMT pathways mediated by Slug and KRTAP2-3. Thus, TGF-β-induced KRTAP2-3 orchestrates cancer cell proliferation and migration by inducing EMT, suggesting motile cancer cells arrested in G1 phase as a target to suppress metastasis.

Free Research Field

常態系口腔科学

Academic Significance and Societal Importance of the Research Achievements

これまで多くの研究者が「増殖をしている細胞が運動する」という通念を持ってきたが、本研究成果により、「増殖をしていない細胞が運動する」という新たな概念を提唱し、基礎細胞生物学におけるパラダイムシフトを起こした点で学術的意義が大きい。また、本研究の成果により新たな診断マーカーならびに治療標的が同定されたため、臨床応用面での波及効果から社会的意義も大きい。