Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer(NSCLC)patients according to the predicted response to c-Met inhibitor...Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer(NSCLC)patients according to the predicted response to c-Met inhibitors(c-Metis),yet the overall clinical benefit of this strategy is quite limited.Notably,c-Met protein overexpression,which occurs in approximately 20–25%of NSCLC patients,has not yet been clearly defined as a clinically useful biomarker.An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking.Herein,we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status.Furthermore,TGF-β1 treatment resulted in SYK transcriptional downregulation,increased Sp1-mediated transcription of FRA1,and restored the mesenchymal state,which conferred resistance to c-Metis.Clinically,a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3%and longer progression-free survival with c-Meti treatment than other patients.SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance.In summary,SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state.Furthermore,our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.展开更多
The stimulator of interferon genes(STING)protein is an important and promising innate immune target for tumor therapy.However,the instability of the agonists of STING and their tendency to cause systemic immune activa...The stimulator of interferon genes(STING)protein is an important and promising innate immune target for tumor therapy.However,the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle.The STING activator,cyclic di-adenosine monophosphate(CDA),produced by the modified Escherichia coli Nissle 1917,shows high antitumor activity and effectively reduces the systemic effects of the“off-target”caused by the activation of the STING pathway.In this study,we used synthetic biological approaches to optimize the translation levels of the diadenylate cyclase that catalyzes CDA synthesis in vitro.We developed 2 engineered strains,CIBT4523 and CIBT4712,for producing high levels of CDA while keeping their concentrations within a range that did not compromise the growth.Although CIBT4712 exhibited stronger induction of the STING pathway corresponding to in vitro CDA levels,it had lower antitumor activity than CIBT4523 in an allograft tumor model,which might be related to the stability of the surviving bacteria in the tumor tissue.CIBT4523 exhibited complete tumor regression,prolonged survival of mice,and rejection of rechallenged tumors,thus,offering new possibilities for more effective tumor therapy.We showed that the appropriate production of CDA in engineered bacterial strains is essential for balancing antitumor efficacy and self-toxicity.展开更多
Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P ...Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P either activates S1 P receptors(S1PR1-5) through "inside-out signaling" or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1 P signaling and its pathogenic roles in diseases as well as in developing modulators of S1 P signaling, including S1 P agonists, S1 P antagonists and sphingosine kinase(SphK) inhibitors.Ceramide and S1 P have been defined as reciprocal regulators of cell fate, and S1 P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1 P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1 P signaling in cancer development(particularly in inflammationassociated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1 P signaling in cancer treatment.展开更多
基金supported by the Natural Science Foundation of China for Innovation Research Group(No.81821005 to M.G.)the National Natural Science Foundation of China(No.81874314 to H.J,No.82173834 to J.A,No.82173202 to X.Z.)+4 种基金the Lingang Laboratory Grant(No.LG202103-02-01 to J.A)the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning(No.2020CXJQ02 to M.G.)Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer(No.2017B030314120 to Y.W.)Guangdong Provincial Natural Science Program(No.2019A1515010900 to X.Z.)GDPH Dengfeng Program(No.DFJH201903&KJ012019444&8197103306 to X.Z.).
文摘Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer(NSCLC)patients according to the predicted response to c-Met inhibitors(c-Metis),yet the overall clinical benefit of this strategy is quite limited.Notably,c-Met protein overexpression,which occurs in approximately 20–25%of NSCLC patients,has not yet been clearly defined as a clinically useful biomarker.An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking.Herein,we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status.Furthermore,TGF-β1 treatment resulted in SYK transcriptional downregulation,increased Sp1-mediated transcription of FRA1,and restored the mesenchymal state,which conferred resistance to c-Metis.Clinically,a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3%and longer progression-free survival with c-Meti treatment than other patients.SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance.In summary,SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state.Furthermore,our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.
基金This work was supported in part by the National Natural Science Foundation of China(21825804)the National Science and Technology Major Project“Key New Drug Creation and Manufacturing Program,”China(2018ZX09711002–019)+2 种基金the Shanghai Municipal Science and Technology Major Project,the Lingang Laboratory(LG202103–02–08)the Shanghai Municipal Science and Technology Major Project,the Natural Science Foundation of China for Innovation Research Group(81821005 to M.G.)the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning(2020CXJQ02).A。
文摘The stimulator of interferon genes(STING)protein is an important and promising innate immune target for tumor therapy.However,the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle.The STING activator,cyclic di-adenosine monophosphate(CDA),produced by the modified Escherichia coli Nissle 1917,shows high antitumor activity and effectively reduces the systemic effects of the“off-target”caused by the activation of the STING pathway.In this study,we used synthetic biological approaches to optimize the translation levels of the diadenylate cyclase that catalyzes CDA synthesis in vitro.We developed 2 engineered strains,CIBT4523 and CIBT4712,for producing high levels of CDA while keeping their concentrations within a range that did not compromise the growth.Although CIBT4712 exhibited stronger induction of the STING pathway corresponding to in vitro CDA levels,it had lower antitumor activity than CIBT4523 in an allograft tumor model,which might be related to the stability of the surviving bacteria in the tumor tissue.CIBT4523 exhibited complete tumor regression,prolonged survival of mice,and rejection of rechallenged tumors,thus,offering new possibilities for more effective tumor therapy.We showed that the appropriate production of CDA in engineered bacterial strains is essential for balancing antitumor efficacy and self-toxicity.
基金financial support from the National Natural Science Foundation of China(91229204)the Major Project of the Chinese National Programs for Fundamental Research and Development(2015CB910304)
文摘Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P either activates S1 P receptors(S1PR1-5) through "inside-out signaling" or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1 P signaling and its pathogenic roles in diseases as well as in developing modulators of S1 P signaling, including S1 P agonists, S1 P antagonists and sphingosine kinase(SphK) inhibitors.Ceramide and S1 P have been defined as reciprocal regulators of cell fate, and S1 P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1 P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1 P signaling in cancer development(particularly in inflammationassociated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1 P signaling in cancer treatment.