The authors regret that an image assembly(copy/paste)error in Figure 3D,in which the image for the organoid of"Primary MiCs"group was erroneously duplicated with an image of primary MICs that was previously ...The authors regret that an image assembly(copy/paste)error in Figure 3D,in which the image for the organoid of"Primary MiCs"group was erroneously duplicated with an image of primary MICs that was previously published.The corrected figure is shown below.As shown in the corrected Figure 3D,this error does not adversely impact the conclusion of the original work.The authors would like to apologise forany inconvenience caused.展开更多
Intestinal cancers are developed from intestinal epithelial stem cells(ISCs)in intestinal crypts through a multi-step process involved in genetic mutations of oncogenes and tumor suppressor genes.ISCs play a key role ...Intestinal cancers are developed from intestinal epithelial stem cells(ISCs)in intestinal crypts through a multi-step process involved in genetic mutations of oncogenes and tumor suppressor genes.ISCs play a key role in maintaining the homeostasis of gut epithelium.In 2009,Sato et al established a three-dimensional culture system,which mimicked the niche microenvironment by employing the niche factors,and successfully grew crypt ISCs into organoids or Mini-guts in vitro.Since then,the intestinal organoid technology has been used to delineate cellular signaling in ISC biology.However,the cultured organoids consist of heterogeneous cell populations,and it was technically challenging to introduce genomic changes into three-dimensional organoids.Thus,there was a technical necessity to develop a twodimensional ISC culture system for effective genomic manipulations.In this study,we established a conditionally immortalized mouse intestinal crypt(ciMIC)cell line by using a piggyBac transposon-based SV40 T antigen expression system.We showed that the ciMICs maintained long-term proliferative activity under two-dimensional niche factor-containing culture condition,retained the biological characteristics of intestinal epithelial stem cells,and could form intestinal organoids in three-dimensional culture.While in vivo cell implantation tests indicated that the ciMICs were non-tumorigenic,the ciMICs overexpressing oncogenic b-catenin and/or KRAS exhibited high proliferative activity and developed intestinal adenoma-like pathological features in vivo.Collectively,these findings strongly suggested that the engineered ciMICs should be used as a valuable tool cell line to dissect the genetic and/or epigenetic underpinnings of intestinal tumorigenesis.展开更多
The inhibitory receptor signal regulatory protein-α(Sirpα)is a myeloid-specific immune checkpoint that engages the“don’t eat me”signal CD47,which is expressed on tumor and normal tissue cells.However,the profile ...The inhibitory receptor signal regulatory protein-α(Sirpα)is a myeloid-specific immune checkpoint that engages the“don’t eat me”signal CD47,which is expressed on tumor and normal tissue cells.However,the profile and regulatory mechanism of Sirpαexpression in tumor-associated macrophages(TAMs)are still not clear.Here,we found that the expression of Sirpαin TAMs increased dynamically with colorectal cancer(CRC)progression.Mechanistically,CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2αfrom the cytoplasm in TAMs.Ap-2αfunctioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at−1396/−1391 in the mouse Elk-1 promoter.Subsequently,the Elk-1 protein bound to two conserved sites,CTTCCTACA(located at−229/−221)and CTTCCTCTC(located at−190/−182),in the mouse Sirpαpromoter and promoted Sirpαexpression in TAMs.Functionally,the macrophage-specific knockout of Ap-2αnotably promoted the phagocytic activity of TAMs and suppressed CRC progression,whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1,which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner.Furthermore,we showed that Elk-1 expression was positively correlated with Sirpαexpression in TAMs and was associated with poor survival in CRC patients.Taken together,our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.展开更多
文摘The authors regret that an image assembly(copy/paste)error in Figure 3D,in which the image for the organoid of"Primary MiCs"group was erroneously duplicated with an image of primary MICs that was previously published.The corrected figure is shown below.As shown in the corrected Figure 3D,this error does not adversely impact the conclusion of the original work.The authors would like to apologise forany inconvenience caused.
文摘Intestinal cancers are developed from intestinal epithelial stem cells(ISCs)in intestinal crypts through a multi-step process involved in genetic mutations of oncogenes and tumor suppressor genes.ISCs play a key role in maintaining the homeostasis of gut epithelium.In 2009,Sato et al established a three-dimensional culture system,which mimicked the niche microenvironment by employing the niche factors,and successfully grew crypt ISCs into organoids or Mini-guts in vitro.Since then,the intestinal organoid technology has been used to delineate cellular signaling in ISC biology.However,the cultured organoids consist of heterogeneous cell populations,and it was technically challenging to introduce genomic changes into three-dimensional organoids.Thus,there was a technical necessity to develop a twodimensional ISC culture system for effective genomic manipulations.In this study,we established a conditionally immortalized mouse intestinal crypt(ciMIC)cell line by using a piggyBac transposon-based SV40 T antigen expression system.We showed that the ciMICs maintained long-term proliferative activity under two-dimensional niche factor-containing culture condition,retained the biological characteristics of intestinal epithelial stem cells,and could form intestinal organoids in three-dimensional culture.While in vivo cell implantation tests indicated that the ciMICs were non-tumorigenic,the ciMICs overexpressing oncogenic b-catenin and/or KRAS exhibited high proliferative activity and developed intestinal adenoma-like pathological features in vivo.Collectively,these findings strongly suggested that the engineered ciMICs should be used as a valuable tool cell line to dissect the genetic and/or epigenetic underpinnings of intestinal tumorigenesis.
基金supported in part by award numbers 81972775(S.Y.),81602628(X.L.)from the National Natural Science Foundation of ChinaSWH2017YQPY-01(S.Y.)and SWH2016ZDCX1002(H.L.)from Southwest Hospital Research and 2018ZDXM016(S.Y.)from the Chongqing Science and Health Joint Fund.
文摘The inhibitory receptor signal regulatory protein-α(Sirpα)is a myeloid-specific immune checkpoint that engages the“don’t eat me”signal CD47,which is expressed on tumor and normal tissue cells.However,the profile and regulatory mechanism of Sirpαexpression in tumor-associated macrophages(TAMs)are still not clear.Here,we found that the expression of Sirpαin TAMs increased dynamically with colorectal cancer(CRC)progression.Mechanistically,CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2αfrom the cytoplasm in TAMs.Ap-2αfunctioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at−1396/−1391 in the mouse Elk-1 promoter.Subsequently,the Elk-1 protein bound to two conserved sites,CTTCCTACA(located at−229/−221)and CTTCCTCTC(located at−190/−182),in the mouse Sirpαpromoter and promoted Sirpαexpression in TAMs.Functionally,the macrophage-specific knockout of Ap-2αnotably promoted the phagocytic activity of TAMs and suppressed CRC progression,whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1,which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner.Furthermore,we showed that Elk-1 expression was positively correlated with Sirpαexpression in TAMs and was associated with poor survival in CRC patients.Taken together,our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.