Epithelial cells activate fibroblasts to promote esophageal cancer development

  • Cancer Cell. 2023 Mar 14;S1535-6108(23)00049-1. doi: 10.1016/j.ccell.2023.03.001.
Yamei Chen  1 ,  Shihao Zhu  1 ,  Tianyuan Liu  1 ,  Shaosen Zhang  1 ,  Junting Lu  1 ,  Wenyi Fan  1 ,  Lin Lin  1 ,  Tao Xiang  1 ,  Jie Yang  1 ,  Xuan Zhao  1 ,  Yiyi Xi  1 ,  Yuling Ma  1 ,  Guoyu Cheng  1 ,  Dongxin Lin  2 ,  Chen Wu  3
Affiliations
  • 1. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
  • 2. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China. Electronic address: [email protected].
  • 3. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; CAMS Oxford Institute, Chinese Academy of Medical Sciences, Beijing 100006, China. Electronic address: [email protected].
PMID: 36963399 DOI: 10.1016/j.ccell.2023.03.001
Abstract

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 transcription 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-β 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.

Keywords
ANXA1; FPR2; cancer-associated fibroblast; esophageal cancer; precancerous lesions.
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