PO.TB10.01 · 肿瘤生物学

香烟烟雾诱导的鞘氨醇-1-磷酸驱动癌相关成纤维细胞活化及食管癌癌变

Cigarette smoke-induced sphingosine-1-phosphate drives cancer-associated fibroblasts activation and esophageal cancer carcinogenesis

编号 2274 展板 23 时间 4/20 09:00–12:00 区域 Section 33 主讲 Jiang Chang, PhD

分会场 Tumorigenesis and Early Microenvironmental Trajectories

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作者与单位 Authors & Affiliations

Xinying Yue¹, Jialing Ma¹, Zifei Yang¹, Yutong Wu¹, Qianqian Su¹, Lina Song¹, Miaoxin Pan¹, Dongxu Li², Qingyi Liu², Shasha Liu¹, Yueping Li¹, Shaokai Zhang³, Siyuan Wang⁴, Li Zhang⁵, Ni Zhang⁵, Wei Ping⁵, Catherine C. L. Wong⁴, Dongxin Lin², Chen Wu², Jiang Chang¹

¹Huazhong University of Science and Technology, Wuhan, China,²Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China,³The Affiliated Cancer Hospital of Zhengzhou University, ZhengZhou, China,⁴Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China,⁵Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

摘要 Abstract

中文摘要

香烟烟雾对肿瘤微环境重塑的代谢影响仍未明确界定。在此，我们基于一项涉及10,716例病例和12,637例对照的基因-吸烟交互作用分析，鉴定出ACER1中一个错义变异，该变异特异性地在吸烟者中赋予了食管鳞状细胞癌（ESCC）的升高风险。功能实验表明，该风险等位基因与尼古丁和苯并[a]芘协同作用，增强ESCC上皮细胞中鞘氨醇-1-磷酸（S1P）的生物合成与分泌。跨多阶段ESCC样本的整合单细胞RNA测序、空间蛋白质组学及多重免疫荧光分析揭示，这种ACER1驱动的鞘脂重编程促进了肌成纤维细胞型癌相关成纤维细胞（myCAFs）的活化。从机制上讲，上皮分泌的S1P在成纤维细胞中启动S1PR3-ERK-AKT信号级联，促进一种促肿瘤的基质状态。药理学抑制S1PR3显著抑制了ESCC在体内的生长。这些发现揭示了驱动食管肿瘤发生中促肿瘤微环境重塑的关键基因-环境交互作用，并凸显了一个可用于早期检测和治疗干预的代谢脆弱点。

查看英文原文 English abstract

The metabolic impact of cigarette smoke on tumor microenvironment remodeling remains poorly defined. Here, we identify a missense variant in ACER1 that confers elevated risk of esophageal squamous cell carcinoma (ESCC) specifically among smokers, based on a gene-smoking interaction analysis involving 10,716 cases and 12,637 controls. Functional assays demonstrate that the risk allele synergizes with nicotine and benzo[a]pyrene to enhance sphingosine-1-phosphate (S1P) biosynthesis and secretion in ESCC epithelial cells. Integrated single-cell RNA sequencing, spatial proteomics, and multiplex immunofluorescence analyses across multi-stage ESCC samples reveal that this ACER1-driven sphingolipid reprogramming promotes the activation of myofibroblastic cancer-associated fibroblasts (myCAFs). Mechanistically, epithelial-secreted S1P engages the S1PR3-ERK-AKT signaling cascade in fibroblasts, promoting a pro-tumorigenic stromal state. Pharmacological inhibition of S1PR3 markedly suppresses ESCC growth in vivo . These findings uncover a critical gene-environment interaction driving pro-tumorigenic microenvironmental remodeling in esophageal tumorigenesis and highlight a metabolic vulnerability for early detection and therapeutic intervention.

利益披露 Disclosure

X. Yue, None.. J. Ma, None.. Z. Yang, None.. Y. Wu, None.. Q. Su, None.. L. Song, None.. M. Pan, None.. D. Li, None.. Q. Liu, None.. S. Liu, None.. Y. Li, None.. S. Zhang, None.. S. Wang, None.. L. Zhang, None.. N. Zhang, None.. W. Ping, None.. C. C. L. Wong, None.. D. Lin, None.. C. Wu, None.. J. Chang, None.

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