上皮细胞激活成纤维细胞促进食管癌的发展

2023-04-09 09:40

鉴于CAF在癌症中的作用，我们的研究强调ANXA1/FPR2信号传导是上皮细胞和成纤维细胞之间促进ESCC的重要串扰机制。

SCI

8 April 2023

Epithelial cells activate fibroblasts to promote esophageal cancer developmen

(Cancer Cell, IF: 38.585)

Yamei Chen, Shihao Zhu, Tianyuan Liu, Shaosen Zhang, Junting Lu, Wenyi Fan, Lin Lin, Tao Xiang, Jie Yang, Xuan Zhao, Yiyi Xi, Yuling Ma, Guoyu Cheng, Dongxin Lin, and Chen Wu

CORRESPONDENCE TO: lindx@cicams.ac.cn, chenwu@cicams.ac.cn

SUMMARY 概要

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-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.

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，低级和高级上皮内瘤变到浸润性癌。然而，癌前病变如何进展为癌症仍然难以捉摸。在这里，我们报告一项全面的单细胞RNA测序和空间转录组学研究，使用来自29例ESCC患者的79个多阶段食管病变标本。我们揭示了，随着病变发展，转录因子KLF4抑制，出现上皮细胞中ANXA1表达的逐渐和显著的丧失。我们证明ANXA1是维持成纤维细胞稳态的成纤维细胞上甲酰肽受体2型（FPR2）的配体。ANXA1的缺失导致正常成纤维细胞不受控制地转化为癌症相关成纤维细胞（CAF），这一过程可以通过恶性上皮细胞分泌的TGF-β增强。鉴于CAF在癌症中的作用，我们的研究强调ANXA1/FPR2信号传导是上皮细胞和成纤维细胞之间促进ESCC的重要串扰机制。