粘液性结直肠腺癌（MCA）是结直肠癌（CRC）的一种独特亚型，具有最具侵袭性的模式，但由于其模糊的病理特征，有效治疗MCA仍然是一个挑战。深入了解细胞水平的转录动力学对于制定专门的 MCA 治疗策略至关重要。我们整合了单细胞 RNA 测序和空间转录组数据，系统地分析了 MCA 肿瘤微环境 (TME)，特别是基质和免疫的相互作用组细胞。此外，进一步应用三维生物打印技术、规范的离体共培养系统和免疫荧光染色来验证 TME 内的细胞通讯网络。本研究确定了参与 MCA 发病机制的关键细胞间相互作用。我们发现 MCA 组织中 FGF7 /THBS1 肌成纤维细胞的浸润增加，与白细胞介导的免疫和 T 细胞活化相关的基因表达减少，表明这些细胞在调节免疫抑制性 TME 中发挥着至关重要的作用。此外，表现出 M2 表型的 MS4A4A 巨噬细胞在肿瘤生态位中富集，并且 MS4A4A 的高表达与队列数据中的不良预后相关。基于配体受体的细胞间通讯分析揭示了MUC1恶性细胞和ZEB1内皮细胞的紧密相互作用，为MCA血管生成和后续转化应用的分子靶点提供了机制信息。我们的研究为肿瘤细胞与基质和免疫细胞之间的通讯提供了新的见解。 MCA 进展期间 TME 中显着富集的细胞，为 MCA 提供了潜在的预后生物标志物和治疗策略。开发了 MCA 的肿瘤微环境分析。 MUC1 肿瘤细胞与 FGF7 /THBS1 肌成纤维细胞相互作用，促进 MCA 发育。 MS4A4A 巨噬细胞在 MCA 中表现出 M2 表型。 ZEB1 内皮细胞参与 MCA 中的 EndMT 过程。© 2024 作者。约翰·威利出版的《临床与转化医学》

Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in-depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies.We integrated single-cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three-dimensional bioprinting technique, canonical ex vivo co-culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME.This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7+/THBS1+ myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte-mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A+ macrophages that exhibit M2-phenotype were enriched in the tumoral niche and high expression of MS4A4A+ was associated with poor prognosis in the cohort data. The ligand-receptor-based intercellular communication analysis revealed the tight interaction of MUC1+ malignant cells and ZEB1+ endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications.Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA.Tumour microenvironment profiling of MCA is developed. MUC1+ tumour cells interplay with FGF7+/THBS1+ myofibroblasts to promote MCA development. MS4A4A+ macrophages exhibit M2 phenotype in MCA. ZEB1+ endotheliocytes engage in EndMT process in MCA.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.