Volume 33, No 8, Aug 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 8, August 2023: 585-603   |  Open Access

ORIGINAL ARTICLES

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

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 Zhong³ , Zehua Jing^3,6 , 6, Qichao Yu^3,6 , Xiaorui Zhou^3,6 , Zhifeng Jiang⁴ , Chunqing Wang^3,6 , Mengnan Cheng^3,6 , Yuan Ji^1,7 , Yingyong Hou⁷ , Rongkui Luo⁷ , Qinqin Li⁸ , LiangWu^3,6 , Jianwen Cheng⁴ , Pengxiang Wang⁴ , Dezhen Guo⁴ , Waidong Huang^3,6 , Junjie Lei^3,6 , Shang Liu³ , Yizhen Yan³ , Yiling Chen³ , Sha Liao^2,3 , Yuxiang Li³ , Haixiang Sun⁴ , Na Yao⁴ , Xiangyu Zhang⁴ , Shiyu Zhang⁴ , Xi Chen³ , Yang Yu⁹ , Yao Li⁹ , Fengming Liu⁹ , Zheng Wang⁴ , Shaolai Zhou⁴ , Huanming Yang³ , 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^1,3,13,* , Xinrong Yang^1,4,* , Ao Chen^1,2,3,14,* , Jian Zhou^1,4,15,*

¹Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China
²BGI-Southwest, BGI-Shenzhen, Chongqing, China
³BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, Guangdong, China
⁴Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
⁵BGI-Hangzhou, Hangzhou, Zhejiang, China
⁶College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
⁷Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
⁸Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁹National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China
¹⁰Guangdong Provincial Key Laboratory of Genome Read and Write, Shenzhen, Guangdong, China
¹¹Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
¹²James D. Watson Institute of Genome Science, Hangzhou, Zhejiang, China
¹³Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen, Guangdong, China
¹⁴JFL-BGI STOmics Center, Jinfeng Laboratory, Chongqing, China
¹⁵State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
^†These authors contributed equally: Liang Wu, Jiayan Yan, Yinqi Bai, Feiyu Chen, Xuanxuan Zou, Jiangshan Xu, Ao Huang
Correspondence: Shiping Liu(liushiping@genomics.cn)Xinrong Yang(yang.xinrong@zs-hospital.sh.cn)Ao Chen(chenao@genomics.cn)Jian Zhou(zhou.jian@zs-hospital.sh.cn)

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.

https://doi.org/10.1038/s41422-023-00831-1

FULL TEXT | PDF

Browse 570