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

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

doi:10.1038/s41422-023-00831-1

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

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 WuJianwen 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

51 Citations (Scopus)

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.

Original language	English
Pages (from-to)	585-603
Number of pages	19
Journal	Cell Research
Volume	33
Issue number	8
DOIs	https://doi.org/10.1038/s41422-023-00831-1
Publication status	Published - Aug 2023
Externally published	Yes

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Wu, L., Yan, J., Bai, Y., Chen, F., Zou, X., Xu, J., Huang, A., Hou, L., Zhong, Y., Jing, Z., Yu, Q., Zhou, X., Jiang, Z., Wang, C., Cheng, M., Ji, Y., Hou, Y., Luo, R., Li, Q., ... Zhou, J. (2023). An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte–tumor cell crosstalk, local immunosuppression and tumor progression. Cell Research, 33(8), 585-603. https://doi.org/10.1038/s41422-023-00831-1

@article{b822ad4c927e4ace991bd95d14c1cc2b,

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

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{\textquoteright} 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.",

author = "Liang Wu and Jiayan Yan and Yinqi Bai and Feiyu Chen and Xuanxuan Zou and Jiangshan Xu and Ao Huang and Liangzhen Hou and Yu Zhong and Zehua Jing and Qichao Yu and Xiaorui Zhou and Zhifeng Jiang and Chunqing Wang and Mengnan Cheng and Yuan Ji and Yingyong Hou and Rongkui Luo and Qinqin Li and Liang Wu and Jianwen Cheng and Pengxiang Wang and Dezhen Guo and Waidong Huang and Junjie Lei and Shang Liu and Yizhen Yan and Yiling Chen and Sha Liao and Yuxiang Li and Haixiang Sun and Na Yao and Xiangyu Zhang and Shiyu Zhang and Xi Chen and Yang Yu and Yao Li and Fengming Liu and Zheng Wang and Shaolai Zhou and Huanming Yang and Shuang Yang and Xun Xu and Longqi Liu and Qiang Gao and Zhaoyou Tang and Xiangdong Wang and Jian Wang and Jia Fan and Shiping Liu and Xinrong Yang and Ao Chen and Jian Zhou",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = aug,

doi = "10.1038/s41422-023-00831-1",

language = "English",

volume = "33",

pages = "585--603",

journal = "Cell Research",

issn = "1001-0602",

publisher = "Nature Publishing Group",

number = "8",

}

Wu, L, Yan, J, Bai, Y, Chen, F, Zou, X, Xu, J, Huang, A, Hou, L, Zhong, Y, Jing, Z, Yu, Q, Zhou, X, Jiang, Z, Wang, C, Cheng, M, Ji, Y, Hou, Y, Luo, R, Li, Q, Wu, L, Cheng, J, Wang, P, Guo, D, Huang, W, Lei, J, Liu, S, Yan, Y, Chen, Y, Liao, S, Li, Y, Sun, H, Yao, N, Zhang, X, Zhang, S, Chen, X, Yu, Y, Li, Y, Liu, F, Wang, Z, Zhou, S, Yang, H, Yang, S, Xu, X, Liu, L, Gao, Q, Tang, Z, Wang, X, Wang, J, Fan, J, Liu, S, Yang, X, Chen, A & Zhou, J 2023, 'An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte–tumor cell crosstalk, local immunosuppression and tumor progression', Cell Research, vol. 33, no. 8, pp. 585-603. https://doi.org/10.1038/s41422-023-00831-1

TY - JOUR

T1 - An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte–tumor cell crosstalk, local immunosuppression and tumor progression

AU - Wu, Liang

AU - Yan, Jiayan

AU - Bai, Yinqi

AU - Chen, Feiyu

AU - Zou, Xuanxuan

AU - Xu, Jiangshan

AU - Huang, Ao

AU - Hou, Liangzhen

AU - Zhong, Yu

AU - Jing, Zehua

AU - Yu, Qichao

AU - Zhou, Xiaorui

AU - Jiang, Zhifeng

AU - Wang, Chunqing

AU - Cheng, Mengnan

AU - Ji, Yuan

AU - Hou, Yingyong

AU - Luo, Rongkui

AU - Li, Qinqin

AU - Wu, Liang

AU - Cheng, Jianwen

AU - Wang, Pengxiang

AU - Guo, Dezhen

AU - Huang, Waidong

AU - Lei, Junjie

AU - Liu, Shang

AU - Yan, Yizhen

AU - Chen, Yiling

AU - Liao, Sha

AU - Li, Yuxiang

AU - Sun, Haixiang

AU - Yao, Na

AU - Zhang, Xiangyu

AU - Zhang, Shiyu

AU - Chen, Xi

AU - Yu, Yang

AU - Li, Yao

AU - Liu, Fengming

AU - Wang, Zheng

AU - Zhou, Shaolai

AU - Yang, Huanming

AU - Yang, Shuang

AU - Xu, Xun

AU - Liu, Longqi

AU - Gao, Qiang

AU - Tang, Zhaoyou

AU - Wang, Xiangdong

AU - Wang, Jian

AU - Fan, Jia

AU - Liu, Shiping

AU - Yang, Xinrong

AU - Chen, Ao

AU - Zhou, Jian

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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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U2 - 10.1038/s41422-023-00831-1

DO - 10.1038/s41422-023-00831-1

M3 - Article

C2 - 37337030

AN - SCOPUS:85162251765

SN - 1001-0602

VL - 33

SP - 585

EP - 603

JO - Cell Research

JF - Cell Research

IS - 8

ER -

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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