Cancer-associated fibroblasts promote esophageal carcinogenesis and lung metastasis by CDH11-mediated extracellular matrix environment remodeling [scRNA-Seq]

Lung metastasis is a major cause of death in patients with esophageal squamous cell carcinoma (ESCC) and its tumor microenvironment (TME) is highly complex; however, the molecular mechanisms of ESCC lung metastasis are unclear. In this study, the first comprehensive single-cell atlas of ESCC lung metastasis is established using single-cell RNA sequencing of 11 patient samples. The findings highlight the dynamic evolutionary patterns of the TME and distinct characteristics of key cellular subpopulations. The immune microenvironment exhibited significant alterations, with a subpopulation of pro-carcinogenic cancer-associated fibroblasts (CAFs) in primary ESCC foci and lung metastases. Notably, calreticulin CDH11 is exclusively expressed in these CAFs and upregulated in conjunction with lung metastasis of ESCC. CDH11 modulates the AKT-related signaling pathway through its interaction with FGFR1, influencing CAF-mediated extracellular matrix remodeling, thereby facilitating metastatic progression. Application of the CDH11 inhibitor, celecoxib, presents a promising new strategy for targeting lung metastasis in ESCC. The molecular mechanisms underlying the lung metastatic microenvironment of ESCC, which are expected to improve the molecular typing accuracy of ESCC lung metastasis to the single-cell level contribute to the development of a precision therapeutic system based on the modulation of the stromal microenvironment, with significant clinical translational potential.