Generating a cancer model using CRISPR/Cas9 system

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07205
• 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: Kitasato University
• Principal Investigator: Nagao Kazuaki 北里大学, 医学部, 講師 (60392487)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 母斑基底細胞癌症候群 / 髄芽腫 / 遺伝子編集 / PTCH1 / ヘッジホッグシグナル伝達系

Outline of Final Research Achievements

Nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome, is an autosomal dominant disorder with an increased incidence of tumors. The PTCH1 gene, responsible for NBCCS, suppresses the hedgehog signaling pathway, which is recognized as one of the important pathways in tumorigenesis. We generated PTCH1-/- induced pluripotent stem cells (iPSCs) from NBCCS patient-derived iPSCs (PTCH1+/-) by gene editing. The proliferation of PTCH1-/- iPSCs was accelerated due to the activation of the hedgehog signaling pathway. When PTCH1-/- iPSCs were subcutaneously injected into immunodeficient mice, the resulting teratomas almost exclusively contained immature ectodermal lineage cells expressing medulloblastoma markers, and the percentages of the area occupied by medulloblastoma-like tissue were larger in PTCH1-/- teratomas than in PTCH1+/- teratomas. These results support the suitability of these gene-edited iPSCs and PTCH1-/- teratomas as models for the formation of tumors.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究は高発がん遺伝病患者由来細胞を用いて積極的にかつ部位特異的に遺伝子変異を導入することでがん化を誘導し、薬剤スクリーニングのモデル細胞として利用するという、世界的に見てもこれまでに例のない極めて独創的かつ斬新的なものである。本研究が進展し、効率よく細胞のがん化が誘導できようになればカウデン病、フォン・ヒッペル・リンドウ病などの他の高発がん遺伝病でも適用が可能であり、オーダーメイド医療の実践に向けて大きく前進するとともに、患者のQOL改善に大きく貢献できることが期待される研究である。