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 Dezhen Guo Waidong Huang Junjie Lei Shang Liu Yizhen Yan Yiling Chen Sha Liao Yuxiang Li Haixiang Sun Na Yao Xiangyu Zhang Shiyu Zhang Xi Chen Yang Yu Yao Li Fengming Liu Zheng Wang Shaolai Zhou Huanming Yang Shuang Yang Xun Xu Longqi Liu Qiang Gao Zhaoyou Tang Xiangdong Wang Jian Wang Jia Fan Shiping Liu Xinrong Yang Ao Chen Jian Zhou 

机构地区：[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 [5]Key Laboratory of Carcinogenesis and Cancer Invasion,Ministry of Education,Shanghai,China [6]BGI-Hangzhou,Hangzhou,Zhejiang,China [7]College of Life Sciences,University of Chinese Academy of Sciences,Beijing,China [8]Department of Pathology,Zhongshan Hospital,Fudan University,Shanghai,China [9]Department of Pathology,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China [10]National Facility for Protein Science in Shanghai,Zhangjiang Lab,Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai,China [11]Guangdong Provincial Key Laboratory of Genome Read and Write,Shenzhen,Guangdong,China [12]Department of Pulmonary and Critical Care Medicine,Zhongshan Hospital,Fudan University,Shanghai,China [13]James D.Watson Institute of Genome Science,Hangzhou,Zhejiang,China [14]Shenzhen Key Laboratory of Single-Cell Omics,BGI-Shenzhen,Shenzhen,Guangdong,China [15]JFL-BGI STOmics Center,Jinfeng Laboratory,Chongqing,China.15State Key Laboratory of Genetic Engineering,Fudan University,Shanghai,China

出　　处：《Cell Research》2023年第8期585-603,共19页细胞研究（英文版）

基　　金：the National Center for Protein Science Shanghai and China National GeneBank for assistance with microscopy.This work was jointly supported by the National Key R&D Program of China(2019YFC1315800,2019YFC1315802,and 2021YFC2501900);the State Key Program of the National Natural Science of China(81830102);the Original Discovery Program of the National Natural Science of China(82150004);the National Natural Science Foundation of China(82341027,81772578,81772551,81872355,81830102,81802991,82150004,and 82072715);the Shanghai Municipal Science and Technology Major Project,the Guangdong Basic and Applied Basic Research Foundation(2021A1515110832);the Shanghai Municipal Health Commission Collaborative Innovation Cluster Project(2019CXJQ02 and 201940075);the Shanghai Municipal Health Commission(2022LJ005);the Shanghai Science and Technology Commission(21140900300);the Shenzhen Key Laboratory of Single-Cell Omics(ZDSYS20190902093613831).

摘　　要：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 500µm-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.

关 键 词：INVASION metastasis STEREO 

分 类 号：R735.7[医药卫生—肿瘤]