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
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
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
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
基于临床肿瘤标本的胃癌异种移植模型(patient derived gastric cancer xenograft,PDGCX)较好地保持了原发肿瘤的异质性,进一步建立模拟临床特征的个体化转移模型对于胃癌研究具有重要意义。本文就PDGCX转移模型的建立方法、影响因素和...基于临床肿瘤标本的胃癌异种移植模型(patient derived gastric cancer xenograft,PDGCX)较好地保持了原发肿瘤的异质性,进一步建立模拟临床特征的个体化转移模型对于胃癌研究具有重要意义。本文就PDGCX转移模型的建立方法、影响因素和评价指标进行综述,归纳筛选胃癌转移相关基因的方法,最终分析PDGCX模型在胃癌治疗靶点的鉴定和转移潜能标志物筛选方面的应用。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
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.
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.
文摘基于临床肿瘤标本的胃癌异种移植模型(patient derived gastric cancer xenograft,PDGCX)较好地保持了原发肿瘤的异质性,进一步建立模拟临床特征的个体化转移模型对于胃癌研究具有重要意义。本文就PDGCX转移模型的建立方法、影响因素和评价指标进行综述,归纳筛选胃癌转移相关基因的方法,最终分析PDGCX模型在胃癌治疗靶点的鉴定和转移潜能标志物筛选方面的应用。
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.
