Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the i...Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regulation in various cell types.3 In this study,we further reported that ZYX promoted migration,invasion,and metastasis of GC cells.Mechanistically,ZYX promoted WNK1 activation and SNAl1 up-regulation,inducing epithelial-mesenchymal transition(EMT)to enhance the mobility of GC cells.Inhibition of WNK1 impaired the mobility of GC cells.Therefore,ZYX/WNK1 could be potential therapeutic targets for GC treatment.展开更多
Synthetic hydrogels are widely used as biomimetic in vitro model systems to understand how cells respond to complex microenvironments. The mechanical properties of hydrogels are deterministic for many cellular behavio...Synthetic hydrogels are widely used as biomimetic in vitro model systems to understand how cells respond to complex microenvironments. The mechanical properties of hydrogels are deterministic for many cellular behaviors, including cell migration, spreading, and differentiation. However, it remains a major challenge to engineer hydrogels that recapture the dynamic mechanical properties of native extracellular matrices. Here, we provide a new hydrogel platform with spatiotemporally tunable mechanical properties to assay and define cellular behaviors under light. The change in the mechanical properties of the hydrogel is effected by a photo-induced switch of the cross-linker fluorescent protein, Dronpa145N, between the tetrameric and monomeric states, which causes minimal changes to the chemical properties of the hydrogel. The mechanical properties can be rapidly and reversibly tuned for multiple cycles using visible light, as confirmed by rheological measurements and atomic force microscopy- based nano-indentation. We further demonstrated real-time and reversible modulation of cell migration behaviors on the hydrogels through photo-induced stiffness switching, with minimal invasion to the cultured cells. Hydrogels with a programmable mechanical history and a spatially defined mechanical hierarchy might serve as an ideal model system to better understand complex cellular functions.展开更多
Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,...Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,and clinical outcomes.Unlike WNT and SHH subgroup MBs,Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options.The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity.In the present study,we demonstrate that Kir2.1,an inwardly-rectifying potassium channel,is highly expressed in non-WNT/SHH MBs,which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway.Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice.Moreover,Kir2.1^(high)/nuclear N2ICD^(high)MBs are associated with the significantly shorter lifespan of the patients.Thus,Kir2.1^(high)/nuclear N2ICD^(high)can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs.Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.展开更多
基金supported by the Chongqing Academician Program(No.cstc2019yszx-jcyjx0008 to Y.W.)The Subject of Health Commission of Hubei Province,China(No.WJ2021M222 to X.-M.W.).
文摘Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regulation in various cell types.3 In this study,we further reported that ZYX promoted migration,invasion,and metastasis of GC cells.Mechanistically,ZYX promoted WNK1 activation and SNAl1 up-regulation,inducing epithelial-mesenchymal transition(EMT)to enhance the mobility of GC cells.Inhibition of WNK1 impaired the mobility of GC cells.Therefore,ZYX/WNK1 could be potential therapeutic targets for GC treatment.
基金We thank Dr. W. Meng for his initial experiments on this project. This work is funded by the National Natural Science Foundation of China (Nos. 21522402, 21474003, 91427304, 11372279, 11572285, 11674153,11374148, and 11334004), the Fundamental Research Funds for the Central Universities (Nos. 020414380070 and 020414380058), the National Basic Research Program of China (Nos. 2012CB921801 and 2013CB834100) and the National High-tech R&D Program of China (No. 2015AA020941).
文摘Synthetic hydrogels are widely used as biomimetic in vitro model systems to understand how cells respond to complex microenvironments. The mechanical properties of hydrogels are deterministic for many cellular behaviors, including cell migration, spreading, and differentiation. However, it remains a major challenge to engineer hydrogels that recapture the dynamic mechanical properties of native extracellular matrices. Here, we provide a new hydrogel platform with spatiotemporally tunable mechanical properties to assay and define cellular behaviors under light. The change in the mechanical properties of the hydrogel is effected by a photo-induced switch of the cross-linker fluorescent protein, Dronpa145N, between the tetrameric and monomeric states, which causes minimal changes to the chemical properties of the hydrogel. The mechanical properties can be rapidly and reversibly tuned for multiple cycles using visible light, as confirmed by rheological measurements and atomic force microscopy- based nano-indentation. We further demonstrated real-time and reversible modulation of cell migration behaviors on the hydrogels through photo-induced stiffness switching, with minimal invasion to the cultured cells. Hydrogels with a programmable mechanical history and a spatially defined mechanical hierarchy might serve as an ideal model system to better understand complex cellular functions.
基金the National Key Research and Development Program of China(2016YFA0101203 to XW Bian and 2017YFC1309004 to Y Wang)the National Natural Science Foundation of China(31991172,81821003 to X.-W.Bian,81402080 to Y.-X.Wang)Chongqing Basic and Frontier Research Project(cstc2018jcyjAX0406 to Y.-X.Wang and cstc2018jcyjAX0168 to S.-Q.Lv).
文摘Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,and clinical outcomes.Unlike WNT and SHH subgroup MBs,Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options.The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity.In the present study,we demonstrate that Kir2.1,an inwardly-rectifying potassium channel,is highly expressed in non-WNT/SHH MBs,which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway.Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice.Moreover,Kir2.1^(high)/nuclear N2ICD^(high)MBs are associated with the significantly shorter lifespan of the patients.Thus,Kir2.1^(high)/nuclear N2ICD^(high)can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs.Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.