复旦大学周俭、陈奥等利用Stereo-seq技术，揭示了人类肝癌侵袭区促进肝细胞-肿瘤细胞串扰、局部免疫抑制和肿瘤进展。相关论文于2023年6月19日发表于国际顶尖学术期刊《细胞研究》杂志上。

利用纳米级分辨率的新型肿瘤边界扫描和数字化模型-空间增强分辨率组学测序(Stereo-seq)，他们在肝癌患者的肿瘤边界周围发现了一个500 μ m宽的区域，称为“侵袭区”。他们在该区域检测到强烈的免疫抑制、代谢重编程和严重受损的肝细胞。他们还发现了位于肿瘤旁边界附近的受损肝细胞亚群，其血清淀粉样蛋白A1和A2(统称为SAAs)的表达增加。相邻恶性细胞中CXCL6的过表达可诱导附近肝细胞中JAK-STAT3通路的激活，从而导致这些肝细胞中SAAs的过表达。此外，侵袭区肝细胞过度表达和分泌SAAs可导致巨噬细胞募集和M2极化，进一步促进局部免疫抑制，可能导致肿瘤进展。另外5组原发性和继发性肝癌患者独立队列(n = 423)的临床关联分析显示，侵袭区过表达SAAs的患者预后较差。

进一步利用小鼠肝肿瘤模型原位进行的体内实验证实，敲低肝细胞中编码SAAs的基因可减少肿瘤周围巨噬细胞的聚集，延缓肿瘤生长。人类癌症患者中一个新的侵袭区的识别和表征不仅增加了对肿瘤侵袭和转移机制的重要理解，而且可能为开发晚期肝癌和其他实体肿瘤的新治疗策略铺平道路。

据介绍，解剖和理解肿瘤生态系统，特别是肿瘤边缘的生态系统对肿瘤细胞的浸润和侵袭具有重要意义，对于探索肿瘤转移机制和开发有效的新治疗方法至关重要。

附：英文原文

Title: An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte–tumor cell crosstalk, local immunosuppression and tumor progression

Author: Wu, Liang, Yan, Jiayan, Bai, Yinqi, Chen, Feiyu, Zou, Xuanxuan, Xu, Jiangshan, Huang, Ao, Hou, Liangzhen, Zhong, Yu, Jing, Zehua, Yu, Qichao, Zhou, Xiaorui, Jiang, Zhifeng, Wang, Chunqing, Cheng, Mengnan, Ji, Yuan, Hou, Yingyong, Luo, Rongkui, Li, Qinqin, Wu, Liang, Cheng, Jianwen, Wang, Pengxiang, Guo, Dezhen, Huang, Waidong, Lei, Junjie, Liu, Shang, Yan, Yizhen, Chen, Yiling, Liao, Sha, Li, Yuxiang, Sun, Haixiang, Yao, Na, Zhang, Xiangyu, Zhang, Shiyu, Chen, Xi, Yu, Yang, Li, Yao, Liu, Fengming, Wang, Zheng, Zhou, Shaolai, Yang, Huanming, Yang, Shuang, Xu, Xun, Liu, Longqi, Gao, Qiang, Tang, Zhaoyou, Wang, Xiangdong, Wang, Jian, Fan, Jia, Liu, Shiping, Yang, Xinrong, Chen, Ao, Zhou, Jian

Issue&Volume: 2023-06-19

Abstract: Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 μm-wide zone centered around the tumor border in patients with liver cancer, referred to as “the invasive zone”. We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs’ overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n=423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

DOI: 10.1038/s41422-023-00831-1

Source: https://www.nature.com/articles/s41422-023-00831-1