Osteosarcoma(OS)is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments.Increasing evidence indicates that SOX2 overexpression is a primary driver of OS.By screeni...Osteosarcoma(OS)is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments.Increasing evidence indicates that SOX2 overexpression is a primary driver of OS.By screening a small-molecule kinase inhibitor library,we identified AKT as a kinase essential for robust SOX2 expression in OS cells.AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels.We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability.Mechanistically,AKT binds to and phosphorylates SOX2 at T116,preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1.Moreover,we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model.In conclusion,we identified a critical role for AKT in promoting SOX2 overexpression,tumor stemness,and chemoresistance in OS,and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.展开更多
Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce dr...Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce drug resistance or recurrence.Patientderived xenograft(PDX)models are widely used to simulate tumor progression and drug responses,serving as translational tools for precision medicine.This study aimed to establish drug-resistant OSCC PDX models.Human OSCC tissues were transplanted into immunodeficient mice and passaged(P1–P2).At P2(tumor volume:40–80 mm^(3)),mice received cisplatin(1 mg/kg,three times/week)with cetuximab(1 mg/kg,weekly),GSK690693(10 mg/kg,five times/week),or rapamycin(4 mg/kg,five times/week).PDX tissues from groups with less-therapeutic response(manifested as larger tumor volumes)were serially passaged to assess treatment efficacy.Tumor tissues with diminished drug sensitivity underwent histopathological analysis and identified stability of their tumor characteristics using hematoxylin–eosin(HE)and immunohistochemical staining after one additional passage and retreatment.Results demonstrated that successive passaging accelerates tumor growth.First-generation treatments showed universal sensitivity.At P2,cisplatin–cetuximab and rapamycin groups remained sensitive,whereas GSK690693 efficacy declined.Continued passaging of GSK690693-treated tumors confirmed resistance,as evidenced by exhibiting enhanced malignant characteristics at histological level.The GSK690693-resistant model was established first,whereas resistant models of other treatment groups were established according to similar protocols.These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution,enabling the development of drug-resistant OSCC models.This study can offer methodological insights for precision therapy of OSCC.展开更多
The patient-derived xenografts (PDX) model is an animal model established by transplanting primary tumors or fresh tumor tissues of patient origin directly into immunodeficient mice, which preserves the heterogeneity ...The patient-derived xenografts (PDX) model is an animal model established by transplanting primary tumors or fresh tumor tissues of patient origin directly into immunodeficient mice, which preserves the heterogeneity and survival microenvironment of the primary tumor and is widely used in preclinical and precision medicine research of tumors. This article reviews the construction of the PDX model of human bladder cancer and the progress of the application of the PDX model in bladder cancer.展开更多
Despite advancing therapeutic treatments,cancer remains the leading cause of death worldwide,with most of its patients developing drug resistance and recurrence after initial treatment.Therefore,incorporating preclini...Despite advancing therapeutic treatments,cancer remains the leading cause of death worldwide,with most of its patients developing drug resistance and recurrence after initial treatment.Therefore,incorporating preclinical models that mimic human cancer biology and drug responses is essential for improving treatment efficacy and prognosis.Patient-derived xenograft(PDX)models,as a promising and reliable preclinical trial platform,retain key features of the original tumor such as gene expression profiles,histopathological features,drug responses,and molecular signatures more faithfully compared with traditional tumor cell line models and cell line-derived xenograft models.Their significant advantages have been the preferred choice in cancer research,especially demonstrating remarkable potential in drug development,clinical combination therapy,and precision medicine.However,the successful construction and effective application of PDX models still face several challenges.In this review,we summarize the details of constructing PDX models and the drivers affecting their success rates,which will provide some theoretical basis for subsequent model optimization.In the meantime,we delineate the strengths and weaknesses of various mature PDX models and other developing preclinical models,including PDX-derived models,organoids,and genetically engineered models.Moreover,we highlight the challenges of newly developed technologies on the PDX models.Finally,we emphasize the innovative usage of PDX models in a variety of cancer studies and offer insights into their prospects.展开更多
Aim:Cell division cycle 25B(CDC25B)belongs to the CDC25 family of phosphatases that regulate cell cycle progression.CDC25B also contributes to tumor initiation and progression,but no connection between CDC25B levels a...Aim:Cell division cycle 25B(CDC25B)belongs to the CDC25 family of phosphatases that regulate cell cycle progression.CDC25B also contributes to tumor initiation and progression,but no connection between CDC25B levels and drug sensitivity in pancreatic cancer has been reported.Based on our finding that bromodomain and extraterminal domain(BET)inhibitors decrease levels of CDC25B,we aim to compare the sensitivity of models expressing contrasting levels of CDC25B to the BET inhibitor JQ1,in pancreatic cancer cell lines in vitro and in patient-derived xenograft(PDX)models of pancreatic ductal adenocarcinoma(PDAC)in vivo.Methods:We compared the efficacy of the standard of care agent gemcitabine with the BET inhibitor JQ1,using alamarBlue assays to determine IC50s of three pancreatic cancer cell lines in vitro.We used immunohistochemistry(IHC)and immunoblot(IB)to detect CDC25B.We also compared the effect of each agent on the progression of PDX models of PDAC in vivo with contrasting levels of CDC25B.Results:Immunohistochemical data demonstrated that levels of CDC25B differed by~2-to 5-fold in cell lines and PDX models used.In vitro data showed that the level of CDC25B paralleled sensitivity to JQ1.Similarly,in vivo data showed that tumors with high-level CDC25B were more sensitive to JQ1 than tumors with lower CDC25B.The combination of JQ1+a pan CDC25 inhibitor was synergistic in gemcitabine-resistant Panc1.gemR cells that had relatively high levels of CDC25B expression compared to parent cells. Conclusion: The data suggest that CDC25B may be an independent indicator of sensitivity to BET inhibitors and that CDC25B may contribute to gemcitabine insensitivity in this tumor type.展开更多
Dear Editor,Pancreatic cancer is a devastating disease ranked as the 4th leading cause of cancer-related deaths in the United States,and its incidence rate is increasing according to the latest statistics.The overall ...Dear Editor,Pancreatic cancer is a devastating disease ranked as the 4th leading cause of cancer-related deaths in the United States,and its incidence rate is increasing according to the latest statistics.The overall survival rates for patients with pan-creatic cancer have not significantly improved over the past thirty years(Siegel et al.,2012;Simard et al.,2012).One of the reasons for the high mortality rates is the high resistance of pancreatic cancer to chemotherapy and radiation.Most patients are diagnosed at late stages of the disease.Approximately 15%-20%of patients diagnosed with pan-creatic cancer are eligible for surgical resection,and 85%of these patients eventually experience relapse and ultimately cancer-related death(Siegel et al.,2012).In recent years,increasing evidence indicates that the fibro-inflammatory stroma is a source of cellular and molecular components contributing to tumor progression and metastasis(Feig et al.,2012;Waghray et al.,2013).Importantly,increased levels of stroma are positively related to a poor prognosis(Erkan et al.,2008).Despite the broader understanding of pancre-atic cancer biology,gemcitabine,a chemotherapeutic approved for pancreatic cancer treatment approximately twenty years ago,still remains the standard of care(Burris et al.,1997).Thus,the development of novel treatment strategies for this devastating disease is urgently needed.展开更多
Treatment options for patients with esophageal squamous cell carcinoma(ESCC)often result in poor prognosis and declining health-related quality of life.Screening FDA-approved drugs for cancer chemoprevention is a prom...Treatment options for patients with esophageal squamous cell carcinoma(ESCC)often result in poor prognosis and declining health-related quality of life.Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy.Here,we found that dronedarone,an antiarrhythmic drug,could inhibit the proliferation of ESCC cells.Moreover,we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells.Through computational docking models and pull-down assays,we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases.We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays.Subsequently,we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone.Furthermore,dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo.Thus,our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention.展开更多
Hepatocellular carcinoma(HCC)has been known as the second common leading cancer worldwide,as it responds poorly to both chemotherapy and medication.Triptolide(TP),a diterpenoid triepoxide,is a promising treatment agen...Hepatocellular carcinoma(HCC)has been known as the second common leading cancer worldwide,as it responds poorly to both chemotherapy and medication.Triptolide(TP),a diterpenoid triepoxide,is a promising treatment agent for its effective anticancer effect on multiple cancers including HCC.However,its clinical application has been limited owing to its severe systemic toxicities,low solubility,and fast elimination in the body.Therefore,to overcome the above obstacles,photo-activatable liposomes(LP)integrated with both photosensitizer Ce6 and chemotherapeutic drug TP(TP/Ce6-LP)was designed in the pursuit of controlled drug release and synergetic photodynamic therapy in HCC therapy.The TP encapsulated in liposomes accumulated to the tumor site due to the enhanced permeability and retention(EPR)effect.Under laser irradiation,the photosensitizer Ce6 generated reactive oxygen species(ROS)and further oxidized the unsaturated phospholipids.In this way,the liposomes were destroyed to release TP.TP/Ce6-LP with NIR laser irradiation(TP/Ce6-LP+L)showed the best antitumor effect both in vitro and in vivo on a patient derived tumor xenograft of HCC(PDXHCC).TP/Ce6-LP significantly reduced the side effects of TP.Furthermore,TP/Ce6-LP+L induced apoptosis through a caspase-3/PARP signaling pathway.Overall,TP/Ce6-LP+L is a novel potential treatment option in halting HCC progression with attenuated toxicity.展开更多
Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain pro...Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.展开更多
Advances in the field of stem cells have led to the development of a technology called organoids.Organoids are cell cluster structures formed by the cultivation of stem cells in a three-dimensional environment in vitr...Advances in the field of stem cells have led to the development of a technology called organoids.Organoids are cell cluster structures formed by the cultivation of stem cells in a three-dimensional environment in vitro,and they can simulate the living environment of cells in vivo.Organoids play an important role in the screening of drugs for tumor therapy.Compared with traditional drug screening models,tumor organoid models derived from patient tumors have higher sensitivity,heterogeneity,and stability and can restore the real situation of tumors more effectively.Researchers have conducted a number of researches on the feasibility of using organoid technology in drug screening.By testing and comparing the effects of antitumor drugs in organoids and primary tumors,we can select the most appropriate treatment drugs for patients.In the past ten years,organoids from dozens of tissues and biological sample banks from several main organs have been established,and a large number of anticancer drugs have been screened out.This article summarizes the advantages and disadvantages of traditional drug screening models,discusses the development history of organoid technology,and reviews the research results on organoids from tumor drug screening.In addition,the combination of organoid technology and other modern biotechnologies is put forward to further promote the role of organoid technology in the medical field.Finally,this article reviews the history,progress,and prospect on organoids from the view of antitumor drug screening.展开更多
基金supporting by the National Natural Science Foundation of China(Grant No.82172964,82141105,82072961,82403066)Shanghai Pujiang Talent Program(2020PJD062).
文摘Osteosarcoma(OS)is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments.Increasing evidence indicates that SOX2 overexpression is a primary driver of OS.By screening a small-molecule kinase inhibitor library,we identified AKT as a kinase essential for robust SOX2 expression in OS cells.AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels.We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability.Mechanistically,AKT binds to and phosphorylates SOX2 at T116,preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1.Moreover,we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model.In conclusion,we identified a critical role for AKT in promoting SOX2 overexpression,tumor stemness,and chemoresistance in OS,and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.
基金National Natural Science Foundation of China,Grant/Award Number:82173399Young Elite Scientists Sponsorship Program by CAST,Grant/Award Number:2022QNRC001+2 种基金Beijing Natural Science Foundation,Grant/Award Number:7252096Beijing Natural Science Foundation-Haidian Original Innovation Joint Fund Project,Grant/Award Number:L222145CAMS&Comparative Medicine Center,PUMC (IACUC approval number:QC24002)
文摘Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce drug resistance or recurrence.Patientderived xenograft(PDX)models are widely used to simulate tumor progression and drug responses,serving as translational tools for precision medicine.This study aimed to establish drug-resistant OSCC PDX models.Human OSCC tissues were transplanted into immunodeficient mice and passaged(P1–P2).At P2(tumor volume:40–80 mm^(3)),mice received cisplatin(1 mg/kg,three times/week)with cetuximab(1 mg/kg,weekly),GSK690693(10 mg/kg,five times/week),or rapamycin(4 mg/kg,five times/week).PDX tissues from groups with less-therapeutic response(manifested as larger tumor volumes)were serially passaged to assess treatment efficacy.Tumor tissues with diminished drug sensitivity underwent histopathological analysis and identified stability of their tumor characteristics using hematoxylin–eosin(HE)and immunohistochemical staining after one additional passage and retreatment.Results demonstrated that successive passaging accelerates tumor growth.First-generation treatments showed universal sensitivity.At P2,cisplatin–cetuximab and rapamycin groups remained sensitive,whereas GSK690693 efficacy declined.Continued passaging of GSK690693-treated tumors confirmed resistance,as evidenced by exhibiting enhanced malignant characteristics at histological level.The GSK690693-resistant model was established first,whereas resistant models of other treatment groups were established according to similar protocols.These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution,enabling the development of drug-resistant OSCC models.This study can offer methodological insights for precision therapy of OSCC.
文摘The patient-derived xenografts (PDX) model is an animal model established by transplanting primary tumors or fresh tumor tissues of patient origin directly into immunodeficient mice, which preserves the heterogeneity and survival microenvironment of the primary tumor and is widely used in preclinical and precision medicine research of tumors. This article reviews the construction of the PDX model of human bladder cancer and the progress of the application of the PDX model in bladder cancer.
基金supported by the National Natural Science Foundation of China(No.82172653)the Intra Institutional Open Fund of School of Medicine,Hunan Normal University(No.KF2022001)+1 种基金the Key Project of Developmental Biology and Breeding from Hunan Province,China(No.2022XKQ0205)The Research Team for Reproduction Health and Translational Medicine of Hunan Normal University(No.2023JC101).
文摘Despite advancing therapeutic treatments,cancer remains the leading cause of death worldwide,with most of its patients developing drug resistance and recurrence after initial treatment.Therefore,incorporating preclinical models that mimic human cancer biology and drug responses is essential for improving treatment efficacy and prognosis.Patient-derived xenograft(PDX)models,as a promising and reliable preclinical trial platform,retain key features of the original tumor such as gene expression profiles,histopathological features,drug responses,and molecular signatures more faithfully compared with traditional tumor cell line models and cell line-derived xenograft models.Their significant advantages have been the preferred choice in cancer research,especially demonstrating remarkable potential in drug development,clinical combination therapy,and precision medicine.However,the successful construction and effective application of PDX models still face several challenges.In this review,we summarize the details of constructing PDX models and the drivers affecting their success rates,which will provide some theoretical basis for subsequent model optimization.In the meantime,we delineate the strengths and weaknesses of various mature PDX models and other developing preclinical models,including PDX-derived models,organoids,and genetically engineered models.Moreover,we highlight the challenges of newly developed technologies on the PDX models.Finally,we emphasize the innovative usage of PDX models in a variety of cancer studies and offer insights into their prospects.
文摘Aim:Cell division cycle 25B(CDC25B)belongs to the CDC25 family of phosphatases that regulate cell cycle progression.CDC25B also contributes to tumor initiation and progression,but no connection between CDC25B levels and drug sensitivity in pancreatic cancer has been reported.Based on our finding that bromodomain and extraterminal domain(BET)inhibitors decrease levels of CDC25B,we aim to compare the sensitivity of models expressing contrasting levels of CDC25B to the BET inhibitor JQ1,in pancreatic cancer cell lines in vitro and in patient-derived xenograft(PDX)models of pancreatic ductal adenocarcinoma(PDAC)in vivo.Methods:We compared the efficacy of the standard of care agent gemcitabine with the BET inhibitor JQ1,using alamarBlue assays to determine IC50s of three pancreatic cancer cell lines in vitro.We used immunohistochemistry(IHC)and immunoblot(IB)to detect CDC25B.We also compared the effect of each agent on the progression of PDX models of PDAC in vivo with contrasting levels of CDC25B.Results:Immunohistochemical data demonstrated that levels of CDC25B differed by~2-to 5-fold in cell lines and PDX models used.In vitro data showed that the level of CDC25B paralleled sensitivity to JQ1.Similarly,in vivo data showed that tumors with high-level CDC25B were more sensitive to JQ1 than tumors with lower CDC25B.The combination of JQ1+a pan CDC25 inhibitor was synergistic in gemcitabine-resistant Panc1.gemR cells that had relatively high levels of CDC25B expression compared to parent cells. Conclusion: The data suggest that CDC25B may be an independent indicator of sensitivity to BET inhibitors and that CDC25B may contribute to gemcitabine insensitivity in this tumor type.
文摘Dear Editor,Pancreatic cancer is a devastating disease ranked as the 4th leading cause of cancer-related deaths in the United States,and its incidence rate is increasing according to the latest statistics.The overall survival rates for patients with pan-creatic cancer have not significantly improved over the past thirty years(Siegel et al.,2012;Simard et al.,2012).One of the reasons for the high mortality rates is the high resistance of pancreatic cancer to chemotherapy and radiation.Most patients are diagnosed at late stages of the disease.Approximately 15%-20%of patients diagnosed with pan-creatic cancer are eligible for surgical resection,and 85%of these patients eventually experience relapse and ultimately cancer-related death(Siegel et al.,2012).In recent years,increasing evidence indicates that the fibro-inflammatory stroma is a source of cellular and molecular components contributing to tumor progression and metastasis(Feig et al.,2012;Waghray et al.,2013).Importantly,increased levels of stroma are positively related to a poor prognosis(Erkan et al.,2008).Despite the broader understanding of pancre-atic cancer biology,gemcitabine,a chemotherapeutic approved for pancreatic cancer treatment approximately twenty years ago,still remains the standard of care(Burris et al.,1997).Thus,the development of novel treatment strategies for this devastating disease is urgently needed.
基金funded by the National Natural Science Foundation of China(No.81872335)Central Plains Science and Technology Innovation Leading Talents(No.224200510015)+2 种基金National Natural Science Youth Foundation(No.81902486)Fundamental Research Project of key scientific research in Henan Province(No.23ZX007)Science and Technology Project of Henan Province(No.212102310187)。
文摘Treatment options for patients with esophageal squamous cell carcinoma(ESCC)often result in poor prognosis and declining health-related quality of life.Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy.Here,we found that dronedarone,an antiarrhythmic drug,could inhibit the proliferation of ESCC cells.Moreover,we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells.Through computational docking models and pull-down assays,we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases.We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays.Subsequently,we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone.Furthermore,dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo.Thus,our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention.
基金supported by China postdoctoral Science Foundation(No.2020M673026)the National Natural Science Foundation of China(Nos.81873248,81673903 and 81773642)+1 种基金Opening Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University(Traditional Chinese Pharmacology,China),Zhejiang Chinese Medical University(No.ZYAOXZ2018014,China)State Key Laboratory of Molecular Engineering of Polymers(2019-06,Fudan University,China)
文摘Hepatocellular carcinoma(HCC)has been known as the second common leading cancer worldwide,as it responds poorly to both chemotherapy and medication.Triptolide(TP),a diterpenoid triepoxide,is a promising treatment agent for its effective anticancer effect on multiple cancers including HCC.However,its clinical application has been limited owing to its severe systemic toxicities,low solubility,and fast elimination in the body.Therefore,to overcome the above obstacles,photo-activatable liposomes(LP)integrated with both photosensitizer Ce6 and chemotherapeutic drug TP(TP/Ce6-LP)was designed in the pursuit of controlled drug release and synergetic photodynamic therapy in HCC therapy.The TP encapsulated in liposomes accumulated to the tumor site due to the enhanced permeability and retention(EPR)effect.Under laser irradiation,the photosensitizer Ce6 generated reactive oxygen species(ROS)and further oxidized the unsaturated phospholipids.In this way,the liposomes were destroyed to release TP.TP/Ce6-LP with NIR laser irradiation(TP/Ce6-LP+L)showed the best antitumor effect both in vitro and in vivo on a patient derived tumor xenograft of HCC(PDXHCC).TP/Ce6-LP significantly reduced the side effects of TP.Furthermore,TP/Ce6-LP+L induced apoptosis through a caspase-3/PARP signaling pathway.Overall,TP/Ce6-LP+L is a novel potential treatment option in halting HCC progression with attenuated toxicity.
基金the National Natural Science Foundation of China(81903666 and 31930015)the Chinese Academy of Sciences(XDB31000000,KFJ-STS-SCYD-304,and K.C.Wong Education Foundation,China)+4 种基金the Science and Technology Department of Yunnan Province (202101AT070301,2019ZF003,202002AA100007,202003AD150008,and 2019FB103China)Project of Innovative Research Team of Yunnan Province(2019HC005China)the Department of Industry and Information Technology of Yunnan Province (2019-YT-053,China)。
文摘Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.
基金This work was supported by:National 13th Five-Year Science and Technology Plan Major Projects of China(2017ZX10203205)National Key R&D Plan(2017YFA0104304)+6 种基金National Natural Science Foundation of China(81770648,81972286)Guangdong Natural Science Foundation(2018A030313259,2015A030312013)Science and Technology Program of Guangdong Province(2017B020209004,20169013,2020B1212060019)Science and Technology Program of Guangzhou City(201508020262)Guangdong Basic and Applied Basic Research Foundation(2019A1515110654,2020A1515010574)the Fundamental Research Funds for the Central Universities(20ykpy38)and China Postdoctoral Science Foundation(2019TQ0369,2020M672987).
文摘Advances in the field of stem cells have led to the development of a technology called organoids.Organoids are cell cluster structures formed by the cultivation of stem cells in a three-dimensional environment in vitro,and they can simulate the living environment of cells in vivo.Organoids play an important role in the screening of drugs for tumor therapy.Compared with traditional drug screening models,tumor organoid models derived from patient tumors have higher sensitivity,heterogeneity,and stability and can restore the real situation of tumors more effectively.Researchers have conducted a number of researches on the feasibility of using organoid technology in drug screening.By testing and comparing the effects of antitumor drugs in organoids and primary tumors,we can select the most appropriate treatment drugs for patients.In the past ten years,organoids from dozens of tissues and biological sample banks from several main organs have been established,and a large number of anticancer drugs have been screened out.This article summarizes the advantages and disadvantages of traditional drug screening models,discusses the development history of organoid technology,and reviews the research results on organoids from tumor drug screening.In addition,the combination of organoid technology and other modern biotechnologies is put forward to further promote the role of organoid technology in the medical field.Finally,this article reviews the history,progress,and prospect on organoids from the view of antitumor drug screening.
