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-spe...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.展开更多
Rice ARGONAUTE2(OsAGO2)is a core component of the rice RNA-induced silencing complex(RISC),which is repressed by Magnaporthe oryzae(M.oryzae)infection.Whether and how OsAGO2-mediated gene silencing plays a role in ric...Rice ARGONAUTE2(OsAGO2)is a core component of the rice RNA-induced silencing complex(RISC),which is repressed by Magnaporthe oryzae(M.oryzae)infection.Whether and how OsAGO2-mediated gene silencing plays a role in rice blast resistance and which sRNAs participate in this process are unknown.Our results indicate that OsAGO2 is a key immune player that manipulates rice defense responses against blast disease.OsAGO2 associates with the 24-nt miR1875 and binds to the promoter region of HEXOKINASE1(OsHXK1),which causes DNA methylation and leads to gene silencing.Our multiple genetic evidence showed that,without M.oryzae infection,OsAGO2/miR1875 RISC promoted OsHXK1 promoter DNA methylation and OsHXK1 silencing;after M.oryzae infection,the reduced OsAGO2/miR1875 led to a relatively activated OsHXK1 expression.OsHXK1 acts as a positive regulator of blast disease resistance that OsHXK1-OE rice exhibited enhanced resistance,whereas Cas9-Oshxk1 rice showed reduced resistance against M.oryzae infection.OsHXK1 may function through its sugar sensor activity as glucose induced defense-related gene expression and reactive oxygen species(ROS)accumulation in Nipponbare and OsHXK1-OE but not in Cas9-Oshxk1 rice.OsAGO2 itself is delicately regulated by OsPRMT5,which senses M.oryzae infection and attenuates OsAGO2-mediated gene silencing through OsAGO2 arginine methylation.Our study reveals an OsPRMT5-OsAGO2/miR1875-OsHXK1 regulatory module that fine tunes the rice defense response to blast disease.展开更多
基金supported by the National Key R&D Program ofChina(Nos.2020YFA0803200,2017YFA0504504,and 2018YFA0107500)National Natural Science Foundation of China Grants(Nos.82003014,82150112,81725014,92168116,31930026,81972599,82173276,81822035)+3 种基金the Key Program for Basic Research of Shanghai(No.19JC1415600)Shanghai Rising-Star Program(Nos.22QA1407200,22QA1407300)Open Research Fund of State Key Laboratory of Genetic Engineering,Fudan University(No.SKLGE2103)the China Postdoctoral Science Foundation(No.2020M671231).
文摘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.
基金supported by the Natural Science Foundation of China(31872040)a Jiangsu Agricultural Science and Technology Innovation Fund(CX(21)3090)to HZ+2 种基金Shandong Province Natural Science Foundation of China(ZR2019PC049)Science and Technology Program of Zaozhuang(2020NS13)National College Students Innovation and Entrepreneurship Training Program(202110904107)to PN。
文摘Rice ARGONAUTE2(OsAGO2)is a core component of the rice RNA-induced silencing complex(RISC),which is repressed by Magnaporthe oryzae(M.oryzae)infection.Whether and how OsAGO2-mediated gene silencing plays a role in rice blast resistance and which sRNAs participate in this process are unknown.Our results indicate that OsAGO2 is a key immune player that manipulates rice defense responses against blast disease.OsAGO2 associates with the 24-nt miR1875 and binds to the promoter region of HEXOKINASE1(OsHXK1),which causes DNA methylation and leads to gene silencing.Our multiple genetic evidence showed that,without M.oryzae infection,OsAGO2/miR1875 RISC promoted OsHXK1 promoter DNA methylation and OsHXK1 silencing;after M.oryzae infection,the reduced OsAGO2/miR1875 led to a relatively activated OsHXK1 expression.OsHXK1 acts as a positive regulator of blast disease resistance that OsHXK1-OE rice exhibited enhanced resistance,whereas Cas9-Oshxk1 rice showed reduced resistance against M.oryzae infection.OsHXK1 may function through its sugar sensor activity as glucose induced defense-related gene expression and reactive oxygen species(ROS)accumulation in Nipponbare and OsHXK1-OE but not in Cas9-Oshxk1 rice.OsAGO2 itself is delicately regulated by OsPRMT5,which senses M.oryzae infection and attenuates OsAGO2-mediated gene silencing through OsAGO2 arginine methylation.Our study reveals an OsPRMT5-OsAGO2/miR1875-OsHXK1 regulatory module that fine tunes the rice defense response to blast disease.
