The tumor microenvironment(TME),including infiltrated immune cells,is known to play an important role in tumor growth;however,the mechanisms underlying tumor immunogenicity have not been fully elucidated.Here,we disco...The tumor microenvironment(TME),including infiltrated immune cells,is known to play an important role in tumor growth;however,the mechanisms underlying tumor immunogenicity have not been fully elucidated.Here,we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment.Based on analyses of patient datasets,we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients.Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME.Mechanistically,SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway,and collagen deposition in the TME hampered immune cell infiltration and activation.Thus,our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.展开更多
Nanog is a newly identified homeodomain gene that functions to sustain the pluripotency of embryonic stem cells.However,the molecular mechanism through which nanog regulates stem cell pluripotency remains unknown.Mous...Nanog is a newly identified homeodomain gene that functions to sustain the pluripotency of embryonic stem cells.However,the molecular mechanism through which nanog regulates stem cell pluripotency remains unknown.Mouse nanog encodes a polypeptide of 305 residues with a divergent homeodomain similar to those in the NK-2 family.The rest ofnanog contains no apparent homology to any known proteins characterized so far.It is hypothesized that nanog encodes a transcription factor that regulates stem cell pluripotency by switching on or off target genes.To test this hypothesis,we constructed fusion proteins between nanog and DNA binding domains of the yeast transcription factor Gal4 and tested the transactivation potentials of these constructs.Our data demonstrate that both regions N- and C- terminal to the homeodomain have transcription activities.Despite the fact that it contains no apparent transactivation motifs,the C-terminal domain is about 7 times as active as the N-terminal one.This unique arrangement of dual transactivators may confer nanog the flexibility and specificity to regulate downstream genes critical for both pluripotency and differentiation of stem cells.展开更多
Retinal ganglion cell(RGC) axons provide the only link between the light sensitive and photon transducing neural retina and visual centers of the brain.RGC axon degeneration occurs in a number of blinding diseases and...Retinal ganglion cell(RGC) axons provide the only link between the light sensitive and photon transducing neural retina and visual centers of the brain.RGC axon degeneration occurs in a number of blinding diseases and the ability to stimulate axon regeneration from surviving ganglion cells could provide the anatomic substrate for restoration of vision.OTX2 is a homeoprotein transcription factor expressed in the retina and previous studies showed that,in response to stress,exogenous OTX2 increases the in vitro and in vivo survival of RGCs.Here we examined and quantified the effects of OTX2 on adult RGC axon regeneration in vitro and in vivo.The results show that exogenous OTX2 stimulates the regrowth of axons from RGCs in cultures of dissociated adult retinal cells and from explants of adult retinal tissue and that RGCs respond directly to OTX2 as regrowth is observed in cultures of purified adult rat RGCs.Importantly,after nerve crush in vivo,we observed a positive effect of OTX2 on the number of regenerating axons up to the optic chiasm within 14 days post crush and a very modest level of acuity absent in control mice.The effect of OTX2 on RGC survival and regeneration is of potential interest for degenerative diseases affecting this cell type.All animal procedures were approved by the local "Comié d'éιthique en expérimentation animale n°59" and authorization n° 00702.01 delivered March 28,2014 by the French "Ministére de l'enseignement supérieur et de la recherche".展开更多
基金This project was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-1-I2M-047,2016-I2M-1-005 and 2019-I2M-1-003)National Science funds of China(82073181,81802870,82102371 and 2017YFA0506200)+4 种基金Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2020-PT310-006,2019XK310002 and 2018TX31001)HY is supported by science funds from Jiangsu Province(BK20211554,BK20170407)the Innovative and Entrepreneurial Team grant(2018-2021)from Jiangsu ProvinceLL is supported by the Chinese Postdoctoral Science Foundation(2019M650564)Innovative and Entrepreneurial Doctor grant(2020-2022)from Jiangsu Province.
文摘The tumor microenvironment(TME),including infiltrated immune cells,is known to play an important role in tumor growth;however,the mechanisms underlying tumor immunogenicity have not been fully elucidated.Here,we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment.Based on analyses of patient datasets,we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients.Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME.Mechanistically,SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway,and collagen deposition in the TME hampered immune cell infiltration and activation.Thus,our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.
基金supported in part by the Tsinghua University BaiRen Scholar Program,NSFC 30270287the 973 Project--2001CB5101 from The Ministry of Science and Technology of China.
文摘Nanog is a newly identified homeodomain gene that functions to sustain the pluripotency of embryonic stem cells.However,the molecular mechanism through which nanog regulates stem cell pluripotency remains unknown.Mouse nanog encodes a polypeptide of 305 residues with a divergent homeodomain similar to those in the NK-2 family.The rest ofnanog contains no apparent homology to any known proteins characterized so far.It is hypothesized that nanog encodes a transcription factor that regulates stem cell pluripotency by switching on or off target genes.To test this hypothesis,we constructed fusion proteins between nanog and DNA binding domains of the yeast transcription factor Gal4 and tested the transactivation potentials of these constructs.Our data demonstrate that both regions N- and C- terminal to the homeodomain have transcription activities.Despite the fact that it contains no apparent transactivation motifs,the C-terminal domain is about 7 times as active as the N-terminal one.This unique arrangement of dual transactivators may confer nanog the flexibility and specificity to regulate downstream genes critical for both pluripotency and differentiation of stem cells.
基金supported by Fovea-Pharmaceuticals,and Global Research Laboratory Program Grant 2009-00424 from the Korean Ministry of Education,Science,and Technology,HOMEOSIGN:ERC-2013-AdG n°339379 and Neuropr Otx:ANR-16-CE16-0003-02。
文摘Retinal ganglion cell(RGC) axons provide the only link between the light sensitive and photon transducing neural retina and visual centers of the brain.RGC axon degeneration occurs in a number of blinding diseases and the ability to stimulate axon regeneration from surviving ganglion cells could provide the anatomic substrate for restoration of vision.OTX2 is a homeoprotein transcription factor expressed in the retina and previous studies showed that,in response to stress,exogenous OTX2 increases the in vitro and in vivo survival of RGCs.Here we examined and quantified the effects of OTX2 on adult RGC axon regeneration in vitro and in vivo.The results show that exogenous OTX2 stimulates the regrowth of axons from RGCs in cultures of dissociated adult retinal cells and from explants of adult retinal tissue and that RGCs respond directly to OTX2 as regrowth is observed in cultures of purified adult rat RGCs.Importantly,after nerve crush in vivo,we observed a positive effect of OTX2 on the number of regenerating axons up to the optic chiasm within 14 days post crush and a very modest level of acuity absent in control mice.The effect of OTX2 on RGC survival and regeneration is of potential interest for degenerative diseases affecting this cell type.All animal procedures were approved by the local "Comié d'éιthique en expérimentation animale n°59" and authorization n° 00702.01 delivered March 28,2014 by the French "Ministére de l'enseignement supérieur et de la recherche".
