Lee Sung Hak, Lee Dagyeong, Choi Junyong, Oh Hye Jeong, Ham In-Hye, Ryu Daeun, Lee Seo-Yeong, Han Dong-Jin, Kim Sunmin, Moon Youngbeen, Song In-Hye, Song Kyo Young, Lee Hyeseong, Lee Seungho, Hur Hoon, Kim Tae-Min
Department of Hospital Pathology, Seoul St. Mary's Hostpital, Collage of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea.
Department of Surgery, Ajou University School of Medicine, Suwon, The Republic of Korea.
Gut. 2025 Apr 7;74(5):714-727. doi: 10.1136/gutjnl-2024-332901.
A spatially resolved, niche-level analysis of tumour microenvironments (TME) can provide insights into cellular interactions and their functional impacts in gastric cancers (GC).
Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells.
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.
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 -expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. fibroblasts and -activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that fibroblasts recruit myeloid cells and stimulate activation in recruited macrophages. The development of immunosuppressive TME by fibroblasts were also validated in syngeneic mouse models.
GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between fibroblasts and -activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance.
对肿瘤微环境（TME）进行空间分辨的、生态位水平的分析，可以深入了解细胞间相互作用及其对胃癌（GC）的功能影响。
我们的目标是将GC生态系统的空间组织转化为涉及恶性、基质和免疫细胞的细胞相互作用的功能景观。
我们使用Visium平台对9个原发性GC样本进行了空间转录组学分析，以描绘GC组织结构内恶性、基质和免疫细胞的转录景观和动态变化，突出细胞间的相互作用及其在TME中的功能后果。
具有显著细胞异质性的GC空间转录组被划分为六个区域隔室。具体而言，富含成纤维细胞的TME分别上调恶性细胞和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态表明，恶性细胞和内皮细胞促进TME细胞的增殖，而成纤维细胞和免疫细胞分别与促癌免疫和抗癌免疫相关。配体-受体分析显示，表达的成纤维细胞通过JAK-STAT3信号通路和肿瘤浸润巨噬细胞中的炎症反应促进肿瘤进展。成纤维细胞和活化巨噬细胞共定位，它们的共同丰度与不良预后相关。我们通过实验验证了成纤维细胞招募髓样细胞并刺激招募的巨噬细胞中的活化。成纤维细胞诱导免疫抑制TME的形成也在同基因小鼠模型中得到验证。
GC空间转录组揭示了涉及多种细胞类型的功能性细胞间相互作用，其中成纤维细胞和活化巨噬细胞之间的相互作用在建立具有潜在临床相关性的免疫抑制GC TME中发挥作用。
