An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte–tumor cell crosstalk, local immunosuppression and tumor progression
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Published:2023-06-19
Issue:8
Volume:33
Page:585-603
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ISSN:1748-7838
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Container-title:Cell Research
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language:en
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Short-container-title:Cell Res
Author:
Wu LiangORCID, Yan Jiayan, Bai Yinqi, Chen Feiyu, Zou Xuanxuan, Xu Jiangshan, Huang Ao, Hou Liangzhen, Zhong YuORCID, Jing ZehuaORCID, 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 HuanmingORCID, Yang Shuang, Xu XunORCID, Liu LongqiORCID, Gao Qiang, Tang Zhaoyou, Wang Xiangdong, Wang Jian, Fan JiaORCID, Liu ShipingORCID, Yang XinrongORCID, Chen AoORCID, Zhou JianORCID
Abstract
AbstractDissecting 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.
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology
Reference68 articles.
1. Ji, A. L. et al. Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma. Cell 182, 497–514.e22 (2020). 2. Lewis, S. M. et al. Spatial omics and multiplexed imaging to explore cancer biology. Nat. Methods 18, 997–1012 (2021). 3. Wu, Y. et al. Spatiotemporal immune landscape of colorectal cancer liver metastasis at single-cell level. Cancer Discov. 12, 134–153 (2022). 4. Schurch, C. M. et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell 182, 1341–1359.e19 (2020). 5. Grunwald, B. T. et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell 184, 5577–5592.e18 (2021).
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