上皮细胞激活成纤维细胞促进食管癌的发展。

IF 44.5 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2023-05-08 DOI:10.1016/j.ccell.2023.03.001

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, Chen Wu

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引用次数: 11

摘要

食管鳞状细胞癌(ESCC)的发展经历了多阶段上皮癌的形成，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，癌前病变如何发展为癌仍是一个谜。在这里，我们报告了对29例ESCC患者79个多期食管病变的单细胞RNA测序和空间转录组学研究。我们发现上皮细胞中由于其转录因子KLF4在病变进展过程中受到抑制，ANXA1的表达逐渐显著下降。我们证明ANXA1是成纤维细胞上甲酰基肽受体2型(FPR2)的配体，维持成纤维细胞的稳态。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(CAFs)，恶性上皮细胞分泌TGF-β可增强这种转化。鉴于CAFs在癌症中的作用，我们的研究强调了ANXA1/FPR2信号是上皮细胞和成纤维细胞之间促进ESCC的重要串扰机制。

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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 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.

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.