A YAP/TAZ-CD54 axis is required for CXCR2−CD44− tumor-specific neutrophils to suppress gastric cancer
Received date: 22 May 2022
Accepted date: 15 Jun 2022
Published date: 15 Jul 2023
Copyright
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.
Key words： neutrophils; YAP; TAZ; gastric cancer
Pingping Nie , Weihong Zhang , Yan Meng , Moubin Lin , Fenghua Guo , Hui Zhang , Zhenzhu Tong , Meng Wang , Fan Chen , Liwei An , Yang Tang , Yi Han , Ruixian Yu , Wenjia Wang , Yuanzhi Xu , Linxin Wei , Zhaocai Zhou , Shi Jiao . 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 . DOI: 10.1093/procel/pwac045
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