Role of Mutant p53 in Cancer Malignancy and Dormant Switch Mechanisms Targeting Refractory Breast Cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19398
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Chiba University
• Principal Investigator: Tanaka Tomoaki 千葉大学, 大学院医学研究院, 教授 (50447299)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 乳がん三次元培養 / 変異P53 / 休眠スイッチ

Outline of Final Research Achievements

To elucidate the underlying mechanisms of mutant p53 in malignant transformation, we investigated the relationship between heterogeneity and malignant transformation of cancer tissues by combining 3D culture system and single cell RNA-seq analysis. As one of the molecular basis for the switch mechanism of cancer malignant transformation and dormancy, we found that mutant p53 activates sterol regulatory element-binding protein 2, a key transcriptional factor in the mevalonate synthesis pathway, and its regulatory mechanism, SREBP cleavage- activated protein. Additionally, downstream, a group of molecules controlling the GGPP pathway and Rho-Rac-Cdc42-mediated polymerization of actin filaments played important roles.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

難治性がんの原因として、休眠状態での生き残りや幹細胞特性からの再増殖が、抗癌剤や放射線治療からのダメージを回避による治療抵抗性、再発・転移のメカニズムとして推定されている。本研究成果は、がん悪性化や休眠のスイッチ機構の分子基盤であり、これまでの学術体系を大きく変革・転換させる可能性が期待できる。特に、「乳がん細胞における特定の悪性形質クラスター」を標的とした新たな治療法の開発へと繋がり、難治性がんの克服が期待できる。