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Abstract：
Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.
摘要：
细胞通讯（CC）通过介导细胞之间的细胞间连接来影响肿瘤的发展。然而,CC在恶性转化中的作用和潜在机制尚不清楚。这里,我们研究了恶性转化过程中CC分子表达的时空异质性。发现尽管紧密连接（TJ）和间隙连接（GJ）都参与维持肿瘤微环境（TME），他们表现出相反的特征。机械上,对于上皮细胞（实质成分），TJ分子的表达在正常癌症转化过程中持续下降,是一种潜在的致癌因子.对于成纤维细胞（间充质成分），GJs的表达在正常癌症转化过程中持续增加,是一种潜在的致癌因子.此外,TJs和GJs的分子谱被用来对结直肠癌（CRC）患者进行分层，其中以高GJ水平和低TJ水平为特征的亚型表现出增强的间充质信号。重要的是,我们认为leiomodin1(LMOD1)是双相的，具有TJ和GJ的功能。LMOD1不仅促进癌症相关成纤维细胞（CAF）的激活，而且还抑制癌细胞中的上皮-间质转化（EMT）程序。总之,这些发现证明了CC的分子异质性，并为进一步理解TME异质性提供了新的见解。
