1.A YAP/TAZ-CD54 axis is required for CXCR2-CD44- tumor-specific neutrophils to suppress 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
Protein & Cell 2023;14(7):513-531
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.
Humans
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Animals
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Mice
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Adaptor Proteins, Signal Transducing/metabolism*
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Transcription Factors/metabolism*
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Stomach Neoplasms/pathology*
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Neutrophils/pathology*
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Signal Transduction/genetics*
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YAP-Signaling Proteins
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Tumor Microenvironment
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Hyaluronan Receptors/genetics*
Result Analysis
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