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.
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.
Cancer Cell. 2023 May 8;41(5):903-918.e8. doi: 10.1016/j.ccell.2023.03.001. Epub 2023 Mar 23.
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.
食管鳞状细胞癌（ESCC）通过多阶段上皮癌形成发展，即从正常上皮、低级别和高级别上皮内瘤变到浸润性癌。然而，癌前病变如何进展为癌仍然难以捉摸。在这里，我们对 29 名 ESCC 患者的 79 个多阶段食管病变进行了全面的单细胞 RNA 测序和空间转录组学研究。我们揭示了上皮细胞中 ANXA1 表达逐渐显著丧失，这是由于其转录因子 KLF4 抑制沿病变进展。我们证明 ANXA1 是成纤维细胞上形成肽受体 2（FPR2）的配体，可维持成纤维细胞的稳态。ANXA1 的缺失导致正常成纤维细胞失控转化为癌相关成纤维细胞（CAF），而恶性上皮细胞分泌的 TGF-β 可增强这种转化。鉴于 CAF 在癌症中的作用，我们的研究强调了 ANXA1/FPR2 信号作为促进 ESCC 的上皮细胞和成纤维细胞之间重要的串扰机制。
