2. Academic Validation
  3. An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression

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

  • Cell Res. 2023 Jun 19. doi: 10.1038/s41422-023-00831-1.
Liang Wu # 1 2 3,  Jiayan Yan # 1 4,  Yinqi Bai # 1 3 5,  Feiyu Chen # 1 4,  Xuanxuan Zou # 2 3 6,  Jiangshan Xu # 3 6,  Ao Huang # 1 4,  Liangzhen Hou 3 6,  Yu Zhong 3,  Zehua Jing 3 6,  Qichao Yu 3 6,  Xiaorui Zhou 3 6,  Zhifeng Jiang 4,  Chunqing Wang 3 6,  Mengnan Cheng 3 6,  Yuan Ji 1 7,  Yingyong Hou 7,  Rongkui Luo 7,  Qinqin Li 8,  Liang Wu 3 6,  Jianwen Cheng 4,  Pengxiang Wang 4,  Dezhen Guo 4,  Waidong Huang 3 6,  Junjie Lei 3 6,  Shang Liu 3,  Yizhen Yan 3,  Yiling Chen 3,  Sha Liao 2 3,  Yuxiang Li 3,  Haixiang Sun 4,  Na Yao 4,  Xiangyu Zhang 4,  Shiyu Zhang 4,  Xi Chen 3,  Yang Yu 9,  Yao Li 9,  Fengming Liu 9,  Zheng Wang 4,  Shaolai Zhou 4,  Huanming Yang 3,  Shuang Yang 1 3 6,  Xun Xu 1 3 10,  Longqi Liu 1 5,  Qiang Gao 1 4,  Zhaoyou Tang 1 4,  Xiangdong Wang 1 11,  Jian Wang 1 3 12,  Jia Fan 1 4,  Shiping Liu 13 14 15,  Xinrong Yang 16 17,  Ao Chen 18 19 20 21,  Jian Zhou 22 23 24
Affiliations

Affiliations

  • 1 Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 BGI-Southwest, BGI-Shenzhen, Chongqing, China.
  • 3 BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, Guangdong, China.
  • 4 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
  • 5 BGI-Hangzhou, Hangzhou, Zhejiang, China.
  • 6 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 7 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 8 Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
  • 10 Guangdong Provincial Key Laboratory of Genome Read and Write, Shenzhen, Guangdong, China.
  • 11 Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 12 James D. Watson Institute of Genome Science, Hangzhou, Zhejiang, China.
  • 13 Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. liushiping@genomics.cn.
  • 14 BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, Guangdong, China. liushiping@genomics.cn.
  • 15 Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen, Guangdong, China. liushiping@genomics.cn.
  • 16 Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. yang.xinrong@zs-hospital.sh.cn.
  • 17 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. yang.xinrong@zs-hospital.sh.cn.
  • 18 Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. chenao@genomics.cn.
  • 19 BGI-Southwest, BGI-Shenzhen, Chongqing, China. chenao@genomics.cn.
  • 20 BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, Guangdong, China. chenao@genomics.cn.
  • 21 JFL-BGI STOmics Center, Jinfeng Laboratory, Chongqing, China. chenao@genomics.cn.
  • 22 Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. zhou.jian@zs-hospital.sh.cn.
  • 23 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. zhou.jian@zs-hospital.sh.cn.
  • 24 State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China. zhou.jian@zs-hospital.sh.cn.
  • # Contributed equally.
PMID: 37337030 DOI: 10.1038/s41422-023-00831-1
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.

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