Patient-derived tumor organoids(PDTOs)shows great potential as a preclinical model.However,the current methods for establishing PDTOs primarily focus on modulating local properties,such as sub-micrometer topographies....Patient-derived tumor organoids(PDTOs)shows great potential as a preclinical model.However,the current methods for establishing PDTOs primarily focus on modulating local properties,such as sub-micrometer topographies.Nevertheless,they neglect to capture the global millimeter or intermediate mesoscale architecture that have been demonstrated to influence tumor response to therapeutic treatment and tumor progression.In this study,we present a rapid technique for generating collagen bundles with an average length of 90±27μm and a mean diameter of 5±1.5μm from tumor tissue debris that underwent mechanical agitation following enzymatic digestion.The collagen bundles were subsequently utilized for the fabrication of biomimetic hydrogels,incorporating microbial transglutaminase(mTG)crosslinked gelatin.These biomimetic hydrogels,referred to as MC-gel,were specifically designed for patient-derived tumor organoids.The lung cancer organoids cultured in MC-gel exhibited larger diameters and higher cell viability compared to those cultured in gels lacking the mesoscale collagen bundle;moreover,their irregular morphology more closely resembled that observed in vivo.The MC-gel-based lung cancer organoids effectively replicated the histology and mutational landscapes observed in the original donor patient’s tumor tissue.Additionally,these lung cancer organoids showed a remarkable similarity in their gene expression and drug response across different matrices.This recently developed model holds great potential for investigating the occurrence,progression,metastasis,and management of tumors,thereby offering opportunities for personalized medicine and customized treatment options.展开更多
基金supported by the National Key R&D Program of China(2019YFA0906000)National Natural Science Foundation of China 82273308+5 种基金this work was supported by the Shenzhen Science and Technology Program(JCYJ20220530112817040,ZDSYS20220606101604009,JHZ20220913142804008)Sanming Project of Medicine in Shenzhen(SZSM201612097)Shenzhen Key Medical Discipline Construction Fund(No.SZXK075)Shenzhen Medical Research Fund(D2301001)Shenzhen High-level Hospital Construction FundSponsored by National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Shenzhen E010122002.
文摘Patient-derived tumor organoids(PDTOs)shows great potential as a preclinical model.However,the current methods for establishing PDTOs primarily focus on modulating local properties,such as sub-micrometer topographies.Nevertheless,they neglect to capture the global millimeter or intermediate mesoscale architecture that have been demonstrated to influence tumor response to therapeutic treatment and tumor progression.In this study,we present a rapid technique for generating collagen bundles with an average length of 90±27μm and a mean diameter of 5±1.5μm from tumor tissue debris that underwent mechanical agitation following enzymatic digestion.The collagen bundles were subsequently utilized for the fabrication of biomimetic hydrogels,incorporating microbial transglutaminase(mTG)crosslinked gelatin.These biomimetic hydrogels,referred to as MC-gel,were specifically designed for patient-derived tumor organoids.The lung cancer organoids cultured in MC-gel exhibited larger diameters and higher cell viability compared to those cultured in gels lacking the mesoscale collagen bundle;moreover,their irregular morphology more closely resembled that observed in vivo.The MC-gel-based lung cancer organoids effectively replicated the histology and mutational landscapes observed in the original donor patient’s tumor tissue.Additionally,these lung cancer organoids showed a remarkable similarity in their gene expression and drug response across different matrices.This recently developed model holds great potential for investigating the occurrence,progression,metastasis,and management of tumors,thereby offering opportunities for personalized medicine and customized treatment options.
