Elucidation of IPMN Oncogenic Mechanisms by CRISPR Screening

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22955
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0905:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kyushu University
• Principal Investigator: OKUMURA Takashi 九州大学, 医学研究院, 共同研究員 (00883422)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: IPMN / 膵オルガノイド / CAF / ニッチ因子 / 癌微小環境 / 膵癌

Outline of Final Research Achievements

Molecular biological elucidation of the developmental process of IPMN and its malignant transformation is expected to lead to early detection and prevention of cancerous transformation of IPMN. We aimed to establish IPMN organoids as a disease model of IPMN by introducing genetic mutations into organoids established from spontaneously carcinogenic pancreatic cancer mice (KC mice). In the process, we established a technique for the establishment of pancreatic cancer organoids and found that the established organoids differ in growth form depending on morphological differences. We found that the dependence on niche factors produced by CAFs differed depending on the morphological classification of the organoids. Furthermore, we found that the dependence on Niche factors in the cancer microenvironment is involved in the sensitivity to anticancer drugs and prognosis.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

IPMNは膵臓に発生する嚢胞性の腫瘍で、IPMNと診断された患者に対して適切な画像診断やフォローアップを行うことで、早期膵癌の診断件数が向上し、膵癌全体の治療成績の改善に大きく寄与する可能性が期待されている。本研究では、膵オルガノイドを用いた形態学的分類を行い、膵癌の分化度ごとの特性を比較・検討したところ、分化度の高い膵癌オルガノイドでは腫瘍の進展において、CAFが産生するNiche因子の一つであるR-spondinに対する依存性がより高いことが明らかになった。これらの結果は、停滞する膵癌新規治療の開発において、個別化医療への応用につながる重要な知見であると考えられる。