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The mechanism of CML leukemia progenitor cells eradication uncovered by Sipa1 deficiency

Sipa1缺陷揭示的CML白血病祖细胞根除机制

基本信息

批准号：
18F18406
负责人：
湊長博
金额：
$ 1.47万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2018
资助国家：
日本
起止时间：
2018-10-12 至 2021-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18F18406/
关键词：
Sipa1 MSCs tumor microenvironment cancer immunity scRNA sequencing Aged Bcr-Abl mutation Colon caner

项目摘要

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.

在这项研究中，我们证实了Sipa 1缺陷（Sipa 1-/-）小鼠对不同的上皮癌细胞（如MC 38肠癌和IPmN胰腺癌）以及慢性髓性白血病（CML）干细胞的抗性增加。我们对肿瘤间质细胞进行了单细胞RNA测序（scRNA-seq）分析，以研究组织间质反应在抗肿瘤机制中的参与。分析结果显示，肿瘤组织间充质基质细胞（MSCs）由FA、FB和FC 3种主要亚型组成，具有不同的基因表达谱。我们通过使用特异性细胞表面标志物的FACS分析定量鉴定了这3种不同的肿瘤MSC亚型。通过分析，我们发现，与野生型（WT）宿主相比，Sipa 1-/-宿主肿瘤组织中的MSC表现出FC和FB亚型的优先增加，这两种亚型分别具有免疫调节和细胞外基质（ECM）调节功能。此外，我们还发现，与WT宿主相比，Sipa 1-/-宿主的肿瘤MSC表现出T细胞趋化因子基因的表达增强。为了验证它们与WT和Sipa 1-/-宿主中的肿瘤细胞和浸润的T细胞的拓扑关系，还进行了组织免疫染色分析以在各种肿瘤组织中原位鉴定这三种MSC亚型。我们的所有结果表明，宿主Sipa 1缺陷导致肿瘤组织中MSC发育模式和基因表达谱的改变，导致针对肿瘤细胞的局部T细胞免疫增强。