Background A spatially resolved, niche-level analysis of tumour microenvironments (TME) can provide insights into cellular interactions and their functional impacts in gastric cancers (GC). Objective Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells. Design We performed spatial transcriptomics on nine primary GC samples using the Visium platform to delineate the transcriptional landscape and dynamics of malignant, stromal and immune cells within the GC tissue architecture, highlighting cellular crosstalks and their functional consequences in the TME. Results GC spatial transcriptomes with substantial cellular heterogeneity were delineated into six regional compartments. Specifically, the fibroblast-enriched TME upregulates epithelial-to-mesenchymal transformation and immunosuppressive response in malignant and TME cells, respectively. Cell type-specific transcriptional dynamics revealed that malignant and endothelial cells promote the cellular proliferations of TME cells, whereas the fibroblasts and immune cells are associated with procancer and anticancer immunity, respectively. Ligand-receptor analysis revealed that CCL2 -expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. CCL2+ fibroblasts and STAT3 -activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that CCL2+ fibroblasts recruit myeloid cells and stimulate STAT3 activation in recruited macrophages. The development of immunosuppressive TME by CCL2+ fibroblasts were also validated in syngeneic mouse models. Conclusion GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between CCL2+ fibroblasts and STAT3 -activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance. Data are available in a public, open access repository. The datasets analysed in the current study are available in the TCGA Research Network () and Gene Expression Omnibus (GEO) with accession ID GSE62254, GSE13861, GSE268999, GSE26901 and GSE28541. The sequencing data have been uploaded to GEO with accession ID GSE251950.

中文翻译：

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胃癌肿瘤微环境的空间解剖揭示了 CCL2 + 成纤维细胞和 STAT3 活化巨噬细胞之间的免疫抑制串扰


背景 对肿瘤微环境 （TME） 进行空间分辨的生态位水平分析可以深入了解细胞相互作用及其对胃癌 （GC） 的功能影响。目的 我们的目标是将 GC 生态系统的空间组织转化为涉及恶性细胞、基质细胞和免疫细胞的细胞相互作用的功能景观。设计我们使用 Visium 平台对 9 个原代 GC 样品进行了空间转录组学研究，以描述 GC 组织结构中恶性、基质和免疫细胞的转录景观和动力学，突出细胞串扰及其在 TME 中的功能后果。结果 具有显著细胞异质性的 GC 空间转录组被划分为 6 个区域区室。具体来说，富含成纤维细胞的 TME 分别上调恶性和 TME 细胞中的上皮-间质转化和免疫抑制反应。细胞类型特异性转录动力学显示，恶性细胞和内皮细胞促进 TME 细胞的细胞增殖，而成纤维细胞和免疫细胞分别与促癌和抗癌免疫相关。配体受体分析显示，表达 CCL2 的成纤维细胞通过 JAK-STAT3 信号传导和肿瘤浸润巨噬细胞的炎症反应促进肿瘤进展。CCL2 + 成纤维细胞和 STAT3 激活的巨噬细胞共定位，它们的共丰度与不良预后相关。我们实验验证了 CCL2 + 成纤维细胞募集骨髓细胞并刺激募集的巨噬细胞中的 STAT3 激活。CCL2 + 成纤维细胞对免疫抑制性 TME 的开发也在同基因小鼠模型中得到验证。 结论 GC 空间转录组揭示了涉及多种细胞类型的功能性细胞串扰，其中 CCL2+ 成纤维细胞与 STAT3 激活的巨噬细胞之间的相互作用在建立免疫抑制性 GC TME 中发挥作用，具有潜在的临床相关性。数据在公共、开放访问存储库中可用。当前研究中分析的数据集可在 TCGA 研究网络 （） 和基因表达综合 （GEO） 中获得，登录号 GSE62254、GSE13861、GSE268999、GSE26901 和 GSE28541。测序数据已上传到 GEO，入藏 ID GSE251950。