Development of next-generation patient-derived xenograft models for precision medicine

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02949
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Ehime University
• Principal Investigator: Takenaka Katsuto 愛媛大学, 医学系研究科, 教授 (30301295)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 患者腫瘍組織移植モデル / 免疫不全マウス / SIRPA / マクロファージ寛容 / がん幹細胞

Outline of Final Research Achievements

The xenograft system developed by immunodeficient mice as an assay system for normal human hematopoietic stem cells is expected to be applied as a model for reproducing human diseases, for stem cell purification of hematologic and solid tumors, and for development of stem cell targeted therapy. In this project, we aimed to develop a PDX model capable of building a general disease recapitulation model that overcomes the problems of current xenograft systems: in a B6 background, Rag2 and IL2Rg deficiency were introduced with Kit mutations for bone marrow niche opening and “complete” by human SIRPA knock-in BRGhSK, a complete next-generation PDX model in which the introduction of “macrophage tolerance” was also completed by human SIRPA knock-in, was successfully established to establish a mouse model for this research project.

Free Research Field

ヒト化患者腫瘍組織移植モデル

Academic Significance and Societal Importance of the Research Achievements

本課題では、これまでの知見と実績をベースに全般的疾患再現モデルを構築可能な患者腫瘍組織移植（PDX）モデルを開発し、腫瘍性幹細胞純化や創薬開発支援の基盤整備をすすめることができた。我々が樹立したPDXモデルは、腫瘍性幹細胞の同定感度が飛躍的に高くなっており、種々の疾患モデルに応用可能で、さらに、樹立された疾患モデルマウスは、ヒト細胞の薬剤感受性試験、再生医療や分子標的治療・遺伝子治療の前臨床試験などに応用可能である。