Tumor cell-intrinsic programmed death-ligand 1(PD-L1)signals mediate tumor initiation,progression and metastasis,but their effects in ameloblastoma(AM)have not been reported.In this comprehensive study,we observed mar...Tumor cell-intrinsic programmed death-ligand 1(PD-L1)signals mediate tumor initiation,progression and metastasis,but their effects in ameloblastoma(AM)have not been reported.In this comprehensive study,we observed marked upregulation of PD-L1 in AM tissues and revealed the robust correlation between elevated PD-L1 expression and increased tumor growth and recurrence rates.Notably,we found that PD-L1 overexpression markedly increased self-renewal capacity and promoted tumorigenic processes and invasion in hTERT^(+)-AM cells,whereas genetic ablation of PD-L1 exerted opposing inhibitory effects.By performing highresolution single-cell profiling and thorough immunohistochemical analyses in AM patients,we delineated the intricate cellular landscape and elucidated the mechanisms underlying the aggressive phenotype and unfavorable prognosis of these tumors.Our findings revealed that hTERT^(+)-AM cells with upregulated PD-L1 expression exhibit increased proliferative potential and stem-like attributes and undergo partial epithelial-mesenchymal transition.This phenotypic shift is induced by the activation of the PI3KAKT-mTOR signaling axis;thus,this study revealed a crucial regulatory mechanism that fuels tumor growth and recurrence.Importantly,targeted inhibition of the PD-L1-PI3K-AKT-mTOR signaling axis significantly suppressed the growth of AM patientderived tumor organoids,highlighting the potential of PD-L1 blockade as a promising therapeutic approach for AM.展开更多
The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells.It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs.Here,...The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells.It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs.Here,we demonstrate that mature low-density neutrophils in colorectal cancer patients abnormally accumulate neutral lipids and induce the reactivation of dormant tumor cells,a process regulated by hepatic stellate cells.Mechanistically,activated hepatic stellate cells increased DGAT1/2-dependent lipid droplet synthesis in low-density neutrophils through the secretion of IL33,thereby maintaining the survival and immunosuppressive function of these neutrophils.The uptake of lipids from lipid-laden low-density neutrophils drives dormant tumor cell reactivation through the potentiation ofβ-oxidation and the stimulation of protumorigenic eicosanoid synthesis.In mouse models,targeting IL33 blocked neutrophil lipid synthesis,decreased the colonization of colorectal cancer cells in the liver,and enhanced the efficacy of immunotherapy.Overall,our study revealed that lipid accumulation in mature low-density neutrophils regulates the growth of dormant tumor cells and antitumor immunity to facilitate colorectal cancer liver metastasis.Targeting IL33 could be a promising therapeutic approach for colorectal cancer liver metastases.展开更多
基金supported by the postdoctoral fellowship program of CPSF(GZC20241270)the China Postdoctoral Science Foundation(2024M762496).
文摘Tumor cell-intrinsic programmed death-ligand 1(PD-L1)signals mediate tumor initiation,progression and metastasis,but their effects in ameloblastoma(AM)have not been reported.In this comprehensive study,we observed marked upregulation of PD-L1 in AM tissues and revealed the robust correlation between elevated PD-L1 expression and increased tumor growth and recurrence rates.Notably,we found that PD-L1 overexpression markedly increased self-renewal capacity and promoted tumorigenic processes and invasion in hTERT^(+)-AM cells,whereas genetic ablation of PD-L1 exerted opposing inhibitory effects.By performing highresolution single-cell profiling and thorough immunohistochemical analyses in AM patients,we delineated the intricate cellular landscape and elucidated the mechanisms underlying the aggressive phenotype and unfavorable prognosis of these tumors.Our findings revealed that hTERT^(+)-AM cells with upregulated PD-L1 expression exhibit increased proliferative potential and stem-like attributes and undergo partial epithelial-mesenchymal transition.This phenotypic shift is induced by the activation of the PI3KAKT-mTOR signaling axis;thus,this study revealed a crucial regulatory mechanism that fuels tumor growth and recurrence.Importantly,targeted inhibition of the PD-L1-PI3K-AKT-mTOR signaling axis significantly suppressed the growth of AM patientderived tumor organoids,highlighting the potential of PD-L1 blockade as a promising therapeutic approach for AM.
基金supported by the National Natural Science Foundation of China,grants 81802326,82473026 and 81871933。
文摘The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells.It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs.Here,we demonstrate that mature low-density neutrophils in colorectal cancer patients abnormally accumulate neutral lipids and induce the reactivation of dormant tumor cells,a process regulated by hepatic stellate cells.Mechanistically,activated hepatic stellate cells increased DGAT1/2-dependent lipid droplet synthesis in low-density neutrophils through the secretion of IL33,thereby maintaining the survival and immunosuppressive function of these neutrophils.The uptake of lipids from lipid-laden low-density neutrophils drives dormant tumor cell reactivation through the potentiation ofβ-oxidation and the stimulation of protumorigenic eicosanoid synthesis.In mouse models,targeting IL33 blocked neutrophil lipid synthesis,decreased the colonization of colorectal cancer cells in the liver,and enhanced the efficacy of immunotherapy.Overall,our study revealed that lipid accumulation in mature low-density neutrophils regulates the growth of dormant tumor cells and antitumor immunity to facilitate colorectal cancer liver metastasis.Targeting IL33 could be a promising therapeutic approach for colorectal cancer liver metastases.
