Epithelial cells activate fibroblasts to promote esophageal cancer development

Esophageal squamous-cell carcinoma (ESCC) develops through multistage epithelial cancer formation, i.e., from normal epithelium, low-and high-grade intraepithelial neoplasia to invasive carcinoma. However, how the precancerous lesions progress to carcinoma remains elusive. Here, we report a comprehensive single -cell RNA sequencing and spatial transcriptomic study of 79 multistage esophageal lesions from 29 patients with ESCC. We reveal a gradual and significant loss of ANXA1 expression in epithelial cells due to its tran-scription factor KLF4 suppression along the lesion progression. We demonstrate that ANXA1 is a ligand to formyl peptide receptor type 2 (FPR2) on fibroblasts that maintain fibroblast homeostasis. Loss of ANXA1 leads to uncontrolled transformation of normal fibroblasts into cancer-associated fibroblasts (CAFs), which can be enhanced by secreted TGF-b from malignant epithelial cells. Given the role of CAFs in cancer, our study underscores ANXA1/FPR2 signaling as an important crosstalk mechanism between epithelial cells and fibroblasts in promoting ESCC.

Automated summary

In this study, a comprehensive analysis of 79 multistage esophageal lesions from 29 ESCC patients was conducted using single-cell RNA sequencing and spatial transcriptomics. The results showed a gradual loss of ANXA1 expression in epithelial cells during lesion progression, which was attributed to the suppression of its transcription factor KLF4. It was also found that ANXA1 is a ligand for fibroblasts and loss of ANXA1 leads to uncontrolled transformation of normal fibroblasts into cancer-associated fibroblasts (CAFs), facilitated by TGF-b secreted by malignant epithelial cells. This highlights the importance of ANXA1/FPR2 signaling in the crosstalk between epithelial cells and fibroblasts in promoting ESCC.