2020 Fiscal Year Annual Research Report
The mechanism of CML leukemia progenitor cells eradication uncovered by Sipa1 deficiency
| Project/Area Number |
18F18406
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| Research Institution | Kyoto University |
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Principal Investigator |
湊 長博 京都大学, 医学研究科, 理事 (40137716)
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| Co-Investigator(Kenkyū-buntansha) |
XU YAN 京都大学, 医学(系)研究科(研究院), 外国人特別研究員
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| Project Period (FY) |
2018-10-12 – 2021-03-31
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| Keywords | Sipa1 / MSCs / tumor microenvironment / cancer immunity |
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| Outline of Annual Research Achievements |
In this study, we have confirmed that Sipa1-deficient (Sipa1-/-) mice showed increased resistance to different epithelial cancer cells such as MC38 intestinal and IPmN pancreatic cancers in addition to chronic myelogenous leukemia (CML) stem cells. We performed single cell RNA sequencing (scRNA-seq) analysis of tumor stromal cells to investigate the involvement of the tissue stromal response in the anti-tumor mechanism. The analysis results revealed that tumor tissue mesenchymal stromal cells (MSCs) consisted of 3 major subtypes, FA, FB, and FC, with distinct gene expression profiles. We identified these 3 different tumor MSC subtypes quantitatively by FACS analysis using specific cell surface markers. With the analysis, we found that MSCs in the tumor tissue of Sipa1-/- hosts showed preferential increase in FC and FB subtypes, which have both immunoregulatory and extracellular matrix (ECM)-regulatory functions, respectively, as compared to those of wild type (WT) hosts. Furthermore, we also found that the tumor MSCs of Sipa1-/- hosts exhibited enhanced expression of T-cell chemokine gene compared to those of WT hosts. In order to verify their topological relation to tumor cells and infiltrated T cells in WT and Sipa1-/- hosts, tissue immuno-staining analysis was also performed to identify the three MSCs subtypes in situ in various tumor tissues.
All of our results have suggested that host Sipa1-deficiency causes altered pattern of MSC development and their gene expression profile in tumor tissues, leading to the enhanced local T-cell immunity against tumor cells.
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| Research Progress Status |
令和2年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
令和2年度が最終年度であるため、記入しない。
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