Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negativ...Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research.In this study,the link between GDF15 and chemotherapy resistance in ESCC was further explored.The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies.ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response.GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2.Through an in vivo study,we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin.Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A.AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A,indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin.The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy,resulting in beneficial therapeutic outcomes.展开更多
Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD dete...Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD detection to provide more accurate management for cancer patients.As new techniques and algorithms have enhanced the performance of MRD detection,the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients.In fact,MRD detection has been shown to achieve better performance than imaging methods.On this basis,rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances.This review summarizes the development of MRD biomarkers,techniques,and strategies for the detection of cancer,and emphasizes the application of MRD detection in solid tumors,particularly for the guidance of clinical treatment.展开更多
Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation ...Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined.Here,we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1(AFB1)targets.Among the most significant hits was the aryl hydrocarbon receptor(AHR),a ligand-binding transcription factor regulating cell metabolism,differentiation,and immunity.展开更多
Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistak...Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistake occurred during the production process in Fig.7 that needs to be corrected.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.展开更多
Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent.However,the lack of a clear understanding of the indications of metformin limits its efficacy.Here,we performed...Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent.However,the lack of a clear understanding of the indications of metformin limits its efficacy.Here,we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin.Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment(T18)compared to those of the untreated cells at day 0(T0)yielded candidate genes.Knockdown of a group of cyclin-dependent kinases(CDKs),including CDK1,CDK4,and CDK6,confirmed the results of the screen.Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo.Although cell cycle parameters were not further altered under the combination treatment,investigation of the metabolome revealed significant changes in cell metabolism,especially with regard to fatty acid oxidation,the tricarboxylic acid cycle and aspartate metabolism.Such changes appeared to be mediated through inhibition of the mTOR pathway.Collectively,our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.展开更多
Human pancreatic neuroendocrine tumors(PanNETs)are a rare,deadly tumor type that is sporadic or arises in the background of a hereditary syndrome.A critical genetic event in sporadic tumors is inactivation of the gene...Human pancreatic neuroendocrine tumors(PanNETs)are a rare,deadly tumor type that is sporadic or arises in the background of a hereditary syndrome.A critical genetic event in sporadic tumors is inactivation of the gene menin 1(MEN1)on chromosome 11,and indeed,PanNETs occur in patients with the hereditary syndrome multiple endocrine neoplasia type 1(MEN1)due to germline mutations in the gene.Here,we review the recent progress in the field of molecular genetics and therapeutic targets of PanNETs.The key genomic alterations,including MEN1,ATRX/DAXX,mammalian target of rapamycin(mTOR),DNA damage and repair associated genes,vascular endothelial growth factor receptor(VEGFR)and SSTRs,and epigenetic aberrations in PanNETs are discussed.In addition,the commonly used preclinical models for PanNETs are enumerated.展开更多
基金the National Key R&D Program of China(No.2021YFC2501004)the National Natural Science Foundation of China(Nos.82172988,81772490 and 81502023)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-1-I2M-014 and 2021-1-I2M-067).
文摘Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research.In this study,the link between GDF15 and chemotherapy resistance in ESCC was further explored.The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies.ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response.GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2.Through an in vivo study,we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin.Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A.AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A,indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin.The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy,resulting in beneficial therapeutic outcomes.
基金supported by National Key R&D Program of China(Nos.2021YFC2500900 and 2021YFC2501004)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-1-I2M-018 and 2021-I2M-1-067)Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2022-RC310-08).
文摘Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD detection to provide more accurate management for cancer patients.As new techniques and algorithms have enhanced the performance of MRD detection,the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients.In fact,MRD detection has been shown to achieve better performance than imaging methods.On this basis,rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances.This review summarizes the development of MRD biomarkers,techniques,and strategies for the detection of cancer,and emphasizes the application of MRD detection in solid tumors,particularly for the guidance of clinical treatment.
基金This work was supported by the National Key R&D Program of China(2018YFC1312100)the National Natural Science Foundation Fund(81772490)+1 种基金the National Key R&D Program of China(2020YFQ002705)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Grants 2016-I2M-1-001,2017-I2M-3-004,and 2019-I2M-1-003).
文摘Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined.Here,we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1(AFB1)targets.Among the most significant hits was the aryl hydrocarbon receptor(AHR),a ligand-binding transcription factor regulating cell metabolism,differentiation,and immunity.
文摘Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistake occurred during the production process in Fig.7 that needs to be corrected.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.
基金supported by the National Natural Science Foundation Fund(81472559,81772490)the National Key R&D Program of China(2020YFC2002705,2018YFC0115204)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Grants 2016-I2M-1-001,2017-I2M-3-004,and 2019-I2M-1-003).
文摘Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent.However,the lack of a clear understanding of the indications of metformin limits its efficacy.Here,we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin.Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment(T18)compared to those of the untreated cells at day 0(T0)yielded candidate genes.Knockdown of a group of cyclin-dependent kinases(CDKs),including CDK1,CDK4,and CDK6,confirmed the results of the screen.Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo.Although cell cycle parameters were not further altered under the combination treatment,investigation of the metabolome revealed significant changes in cell metabolism,especially with regard to fatty acid oxidation,the tricarboxylic acid cycle and aspartate metabolism.Such changes appeared to be mediated through inhibition of the mTOR pathway.Collectively,our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.
基金supported by the National Outstanding Youth Science Fund Project of National Natural Science Foundation of China(82225033)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-067)Non-profit central research institute fund of Chinese Academy of Medical Sciences(2022-RC310-08).
文摘Human pancreatic neuroendocrine tumors(PanNETs)are a rare,deadly tumor type that is sporadic or arises in the background of a hereditary syndrome.A critical genetic event in sporadic tumors is inactivation of the gene menin 1(MEN1)on chromosome 11,and indeed,PanNETs occur in patients with the hereditary syndrome multiple endocrine neoplasia type 1(MEN1)due to germline mutations in the gene.Here,we review the recent progress in the field of molecular genetics and therapeutic targets of PanNETs.The key genomic alterations,including MEN1,ATRX/DAXX,mammalian target of rapamycin(mTOR),DNA damage and repair associated genes,vascular endothelial growth factor receptor(VEGFR)and SSTRs,and epigenetic aberrations in PanNETs are discussed.In addition,the commonly used preclinical models for PanNETs are enumerated.
