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

作者：Liang Wu, Jiayan Yan, Yinqi Bai, Feiyu Chen, Xuanxuan Zou, Jiangshan Xu, Ao Huang, Liangzhen Hou, Yu Zhong, Zehua Jing, Qichao Yu, Xiaorui Zhou, Zhifeng Jiang, Chunqing Wang, Mengnan Cheng, Yuan Ji, Yingyong Hou, Rongkui Luo, Qinqin Li, Liang Wu, Jianwen Cheng, Pengxiang Wang, De‐Zhen Guo, Waidong Huang, Junjie Lei, Shang Liu, Shang Liu, Yizhen Yan, Yi‐Ling Chen, Yuxiang Li, Yuxiang Li, Haixiang Sun, Na Yao, Shiyu Zhang, Shiyu Zhang, Xi Chen, Yang Yu, Fengming Liu, Fengming Liu, Zheng Wang, Shao‐Lai Zhou, Shuang Yang, Shuang Yang, Xun Xu, Longqi Liu, Qiang Gao, Xiangdong Wang, Xiangdong Wang, Jian Wang, Jia Fan, Shiping Liu, Shiping Liu, Xin‐Rong Yang, Ao Chen, Jian Zhou · 发表于：Cell Research · 年份：2023 · DOI：10.1038/s41422-023-00831-1 · 被引用次数：237 · 研究领域：Single-cell and spatial transcriptomics、Cancer Genomics and Diagnostics、Mathematical Biology Tumor Growth

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 w...