Distinct regulatory mechanisms of mitochondrial stress induced SASP in pancreatic exocrine regeneration and cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 20K20390
• Project/Area Number (Other): 18H05384 (2018-2019)
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund (2020); Single-year Grants (2018-2019)
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kyoto University
• Principal Investigator: Yoshiya Kawaguchi 京都大学, iPS細胞研究所, 教授 (60359792)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Keywords: SASP / 膵癌 / マウスモデル

Outline of Final Research Achievements

In the cell community of three-dimensional organs, there exist rules that govern cell behavior. In this study, we aimed to get a clue to establish new therapeutic methods for pancreatic cancer by revealing the distinct rules in the cell community of pancreatic regeneration and cancer in mice. Senescence associated secretory phenotype (SASP) is an intercellular response mediated by the secreted proteins from the stress-induced senescent cells. We found that SASP is transiently activated and stimulated the proliferation of surrounding cells in the regeneration process after pancreatic acinar cellular stress, and stressed cells are gradually removed from the tissue. On the other hand, stressed cells were sustained and prolonged SASP accelerated tumor progression in murine oncogenic model.

Free Research Field

外科学　発生生物学

Academic Significance and Societal Importance of the Research Achievements

マウス膵外分泌細胞に対する２種類のミトコンドリアストレスにより、再生モデルと癌モデルに共通した分子によるSASPが惹起された。SASP分子に対する中和抗体やSASP下流シグナルの阻害化合物の投与により、癌腫進行が著明に阻害された。再生と癌でのSASP持続期間の違いは、PDL1発現による免疫回避機構活性化期間の違いが関与する可能性がある。以上の成果は、慢性炎症による癌進行メカニズムの責任分子解明に貢献しており、新たな治療ターゲットとなり得ると考えられる。