Cancer cell membrane(CCM)derived nanotechnology functionalizes nanoparticles(NPs)to recognize homologous cells,exhibiting translational potential in accurate tumor therapy.However,these nanoplatforms are majorly gener...Cancer cell membrane(CCM)derived nanotechnology functionalizes nanoparticles(NPs)to recognize homologous cells,exhibiting translational potential in accurate tumor therapy.However,these nanoplatforms are majorly generated from fixed cell lines and are typically evaluated in cell line-derived subcutaneous-xenografts(CDX),ignoring the tumor heterogeneity and differentiation from inter-and intra-individuals and microenvironments between heterotopic-and orthotopic-tumors,limiting the therapeutic efficiency of such nanoplatforms.Herein,various biomimetic nanoplatforms(CCM-modified gold@Carbon,i.e.,Au@C-CCM)were fabricated by coating CCMs of head and neck squamous cell carcinoma(HNSCC)cell lines and patient-derived cells on the surface of Au@C NP.The generated Au@C-CCMs were evaluated on corresponding CDX,tongue orthotopic xenograft(TOX),immunecompetent primary and distant tumor models,and patient-derived xenograft(PDX)models.The Au@C-CCM generates a photothermal conversion efficiency up to 44.2% for primary HNSCC therapy and induced immunotherapy to inhibit metastasis via photothermal therapy-induced immunogenic cell death.The homologous CCM endowed the nanoplatforms with optimal targeting properties for the highest therapeutic efficiency,far above those with mismatched CCMs,resulting in distinct tumor ablation and tumor growth inhibition in all four models.This work reinforces the feasibility of biomimetic NPs combining modular designed CMs and functional cores for customized treatment of HNSCC,can be further extended to other malignant tumors therapy.展开更多
Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas(HNSCCs);however,it provides restricted clinical benefits,and its response duration is limited by drug resistance.Here,we conducted ra...Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas(HNSCCs);however,it provides restricted clinical benefits,and its response duration is limited by drug resistance.Here,we conducted randomized“Phase II-like clinical trials”of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab(e.g.,amplification of ANKH,up-regulation of PARP3).After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort(61 PDX models),we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms.Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs,including the emergence of subclones with strongly activated RAS/MAPK.Extending these insights,we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo.Beyond revealing intrinsic resistance biomarkers,our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.展开更多
基金funded by The National Natural Science Foundation of China(81872199)Key Program of National Natural Science Foundation of China(82030085)+4 种基金The National Key Research and Development Program of China(2017YFC0908500)The National Natural Science Foundation of China(82002853)China Postdoctoral Science Foundation(2019M661565)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20212300,SSMU-ZLCX20180500)funded by“Shuguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(19SG13)。
文摘Cancer cell membrane(CCM)derived nanotechnology functionalizes nanoparticles(NPs)to recognize homologous cells,exhibiting translational potential in accurate tumor therapy.However,these nanoplatforms are majorly generated from fixed cell lines and are typically evaluated in cell line-derived subcutaneous-xenografts(CDX),ignoring the tumor heterogeneity and differentiation from inter-and intra-individuals and microenvironments between heterotopic-and orthotopic-tumors,limiting the therapeutic efficiency of such nanoplatforms.Herein,various biomimetic nanoplatforms(CCM-modified gold@Carbon,i.e.,Au@C-CCM)were fabricated by coating CCMs of head and neck squamous cell carcinoma(HNSCC)cell lines and patient-derived cells on the surface of Au@C NP.The generated Au@C-CCMs were evaluated on corresponding CDX,tongue orthotopic xenograft(TOX),immunecompetent primary and distant tumor models,and patient-derived xenograft(PDX)models.The Au@C-CCM generates a photothermal conversion efficiency up to 44.2% for primary HNSCC therapy and induced immunotherapy to inhibit metastasis via photothermal therapy-induced immunogenic cell death.The homologous CCM endowed the nanoplatforms with optimal targeting properties for the highest therapeutic efficiency,far above those with mismatched CCMs,resulting in distinct tumor ablation and tumor growth inhibition in all four models.This work reinforces the feasibility of biomimetic NPs combining modular designed CMs and functional cores for customized treatment of HNSCC,can be further extended to other malignant tumors therapy.
基金The National Key Research and Development Program of China(2017YFC0908500)The National Natural Science Foundation of China(81872199)+1 种基金grants from Key Program of National Natural Science Foundation of China(82030085)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20212300,SSMUZLCX20180500).
文摘Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas(HNSCCs);however,it provides restricted clinical benefits,and its response duration is limited by drug resistance.Here,we conducted randomized“Phase II-like clinical trials”of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab(e.g.,amplification of ANKH,up-regulation of PARP3).After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort(61 PDX models),we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms.Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs,including the emergence of subclones with strongly activated RAS/MAPK.Extending these insights,we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo.Beyond revealing intrinsic resistance biomarkers,our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.
