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

在这项研究中，我们已经证实Sipa1缺陷（Sipa1-/-）小鼠除了对慢性髓性白血病（CML）干细胞外，还表现出对不同上皮癌细胞（如MC38肠癌和IPmN胰腺癌）的抗性增强。我们对肿瘤基质细胞进行了单细胞RNA测序（scRNA-seq）分析，以探讨组织基质反应在抗肿瘤机制中的作用。分析结果显示，肿瘤组织间充质基质细胞（MSCs）由FA、FB和FC 3个主要亚型组成，具有不同的基因表达谱。我们使用特定的细胞表面标记物通过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，Sipa1-/-宿主肿瘤组织中的MSCs优先增加FC和FB亚型，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，Sipa1-/-宿主的肿瘤间充质干细胞的t细胞趋化因子基因表达增强。为了验证它们与WT和Sipa1-/-宿主的肿瘤细胞和浸润T细胞的拓扑关系，我们还进行了组织免疫染色分析，在不同的肿瘤组织中原位鉴定了三种MSCs亚型。我们所有的结果都表明，宿主sipa1缺陷导致肿瘤组织中MSC发育模式及其基因表达谱的改变，导致局部t细胞对肿瘤细胞的免疫增强。

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.