A YAP/TAZ-CD54 axis is required for CXCR2<sup>−</sup>CD44<sup>−</sup> tumor-specific neutrophils to suppress gastric cancer

doi:10.1093/procel/pwac045

Protein Cell

2023, Vol. 14

Issue (7) : 513-531 https://doi.org/10.1093/procel/pwac045

RESEARCH ARTICLE

A YAP/TAZ-CD54 axis is required for CXCR2⁻CD44⁻ tumor-specific neutrophils to suppress gastric cancer

Pingping Nie^1,², Weihong Zhang^3,⁴, Yan Meng⁵, Moubin Lin⁶, Fenghua Guo⁷, Hui Zhang², Zhenzhu Tong^1,², Meng Wang², Fan Chen^1,², Liwei An³, Yang Tang³, Yi Han³, Ruixian Yu², Wenjia Wang², Yuanzhi Xu⁸, Linxin Wei⁵(

), Zhaocai Zhou^2,⁹(

), Shi Jiao²(

)

¹. CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
². State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China
³. Tongji University Cancer Center, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai 200072, China
⁴. Postdoctoral Station of Clinical Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
⁵. Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
⁶. Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
⁷. Department of General Surgery, Hua’shan Hospital, Fudan University Shanghai Medical College, Shanghai 200040, China
⁸. Department of Stomatology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
⁹. Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China

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Abstract

As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44⁻CXCR2⁻ neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54⁺ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54⁺ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54⁺ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.

Keywords neutrophils YAP TAZ gastric cancer

Corresponding Author(s): Linxin Wei,Zhaocai Zhou,Shi Jiao

Issue Date: 18 July 2023

Cite this article:

Pingping Nie,Weihong Zhang,Yan Meng, et al. A YAP/TAZ-CD54 axis is required for CXCR2⁻CD44⁻ tumor-specific neutrophils to suppress gastric cancer[J]. Protein Cell, 2023, 14(7): 513-531.

URL:

https://academic.hep.com.cn/pac/EN/10.1093/procel/pwac045
https://academic.hep.com.cn/pac/EN/Y2023/V14/I7/513

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