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Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer
The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5(+) intestinal stem cells (ISCs). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growt...
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| Published in: | Nature (London) 2015-10, Vol.526 (7575), p.715-718 |
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| creator | Gregorieff, Alex Liu, Yu Inanlou, Mohammad R Khomchuk, Yuliya Wrana, Jeffrey L |
| description | The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5(+) intestinal stem cells (ISCs). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivo Yap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation. |
| doi_str_mv | 10.1038/nature15382 |
| format | article |
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However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivo Yap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature15382</identifier><identifier>PMID: 26503053</identifier><language>eng</language><publisher>England</publisher><subject>Adaptor Proteins, Signal Transducing - deficiency ; Adaptor Proteins, Signal Transducing - metabolism ; Adenoma - metabolism ; Adenoma - pathology ; Animals ; Cell Cycle Proteins ; Cell Differentiation - radiation effects ; Cell Survival - radiation effects ; Cell Transformation, Neoplastic ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Disease Models, Animal ; Epiregulin - metabolism ; ErbB Receptors - metabolism ; Female ; Homeostasis - radiation effects ; Intestinal Mucosa - metabolism ; Intestines - cytology ; Intestines - radiation effects ; Male ; Mice ; Neoplastic Stem Cells - cytology ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Organoids - metabolism ; Paneth Cells - cytology ; Paneth Cells - radiation effects ; Phosphoproteins - deficiency ; Phosphoproteins - metabolism ; Protein-Serine-Threonine Kinases - metabolism ; Radiation, Ionizing ; Receptors, G-Protein-Coupled - metabolism ; Regeneration - radiation effects ; Stem Cells - cytology ; Stem Cells - metabolism ; Stem Cells - radiation effects ; Wnt Signaling Pathway</subject><ispartof>Nature (London), 2015-10, Vol.526 (7575), p.715-718</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c289t-8efdf2d484039b9b29b887d0f8321dc7ca2cd020ddefdc31c5adb6ddd68f9c2e3</citedby><cites>FETCH-LOGICAL-c289t-8efdf2d484039b9b29b887d0f8321dc7ca2cd020ddefdc31c5adb6ddd68f9c2e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26503053$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gregorieff, Alex</creatorcontrib><creatorcontrib>Liu, Yu</creatorcontrib><creatorcontrib>Inanlou, Mohammad R</creatorcontrib><creatorcontrib>Khomchuk, Yuliya</creatorcontrib><creatorcontrib>Wrana, Jeffrey L</creatorcontrib><title>Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer</title><title>Nature (London)</title><addtitle>Nature</addtitle><description>The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5(+) intestinal stem cells (ISCs). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivo Yap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation.</description><subject>Adaptor Proteins, Signal Transducing - deficiency</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adenoma - metabolism</subject><subject>Adenoma - pathology</subject><subject>Animals</subject><subject>Cell Cycle Proteins</subject><subject>Cell Differentiation - radiation effects</subject><subject>Cell Survival - radiation effects</subject><subject>Cell Transformation, Neoplastic</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Disease Models, Animal</subject><subject>Epiregulin - metabolism</subject><subject>ErbB Receptors - metabolism</subject><subject>Female</subject><subject>Homeostasis - radiation effects</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestines - cytology</subject><subject>Intestines - radiation effects</subject><subject>Male</subject><subject>Mice</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Organoids - metabolism</subject><subject>Paneth Cells - cytology</subject><subject>Paneth Cells - radiation effects</subject><subject>Phosphoproteins - deficiency</subject><subject>Phosphoproteins - metabolism</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Radiation, Ionizing</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Regeneration - radiation effects</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - metabolism</subject><subject>Stem Cells - radiation effects</subject><subject>Wnt Signaling Pathway</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNpN0E1LxDAQh_EgiruunrxLjspSnSR9SY-y-AYLXvQgHkqamZZKm5YkK_jtd2VVPM3lN__Dw9i5gGsBSt84EzeeRKa0PGBzkRZ5kua6OGRzAKkT0CqfsZMQPgAgE0V6zGYyz0BBpubs_c1MCdJEDslF7mnyY-vNMHSu5WPD163PLpdXPEQauKW-Dxx990mBdy5SiJ0z_e6rJUfexG503Djk1jhL_pQdNaYPdPZzF-z1_u5l9Zisnx-eVrfrxEpdxkRTg43EVKegyrqsZVlrXSA0WkmBtrBGWgQJiDtolbCZwTpHxFw3pZWkFmy537V-DMFTU02-G4z_qgRU34mqf4l2-mKvp009EP7Z3yZqC2rPZQw</recordid><startdate>20151029</startdate><enddate>20151029</enddate><creator>Gregorieff, Alex</creator><creator>Liu, Yu</creator><creator>Inanlou, Mohammad R</creator><creator>Khomchuk, Yuliya</creator><creator>Wrana, Jeffrey L</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20151029</creationdate><title>Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer</title><author>Gregorieff, Alex ; Liu, Yu ; Inanlou, Mohammad R ; Khomchuk, Yuliya ; Wrana, Jeffrey L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c289t-8efdf2d484039b9b29b887d0f8321dc7ca2cd020ddefdc31c5adb6ddd68f9c2e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adaptor Proteins, Signal Transducing - deficiency</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adenoma - metabolism</topic><topic>Adenoma - pathology</topic><topic>Animals</topic><topic>Cell Cycle Proteins</topic><topic>Cell Differentiation - radiation effects</topic><topic>Cell Survival - radiation effects</topic><topic>Cell Transformation, Neoplastic</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - pathology</topic><topic>Disease Models, Animal</topic><topic>Epiregulin - metabolism</topic><topic>ErbB Receptors - metabolism</topic><topic>Female</topic><topic>Homeostasis - radiation effects</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestines - cytology</topic><topic>Intestines - radiation effects</topic><topic>Male</topic><topic>Mice</topic><topic>Neoplastic Stem Cells - cytology</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Organoids - metabolism</topic><topic>Paneth Cells - cytology</topic><topic>Paneth Cells - radiation effects</topic><topic>Phosphoproteins - deficiency</topic><topic>Phosphoproteins - metabolism</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Radiation, Ionizing</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Regeneration - radiation effects</topic><topic>Stem Cells - cytology</topic><topic>Stem Cells - metabolism</topic><topic>Stem Cells - radiation effects</topic><topic>Wnt Signaling Pathway</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gregorieff, Alex</creatorcontrib><creatorcontrib>Liu, Yu</creatorcontrib><creatorcontrib>Inanlou, Mohammad R</creatorcontrib><creatorcontrib>Khomchuk, Yuliya</creatorcontrib><creatorcontrib>Wrana, Jeffrey L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gregorieff, Alex</au><au>Liu, Yu</au><au>Inanlou, Mohammad R</au><au>Khomchuk, Yuliya</au><au>Wrana, Jeffrey L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer</atitle><jtitle>Nature (London)</jtitle><addtitle>Nature</addtitle><date>2015-10-29</date><risdate>2015</risdate><volume>526</volume><issue>7575</issue><spage>715</spage><epage>718</epage><pages>715-718</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5(+) intestinal stem cells (ISCs). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivo Yap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation.</abstract><cop>England</cop><pmid>26503053</pmid><doi>10.1038/nature15382</doi><tpages>4</tpages></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - deficiency Adaptor Proteins, Signal Transducing - metabolism Adenoma - metabolism Adenoma - pathology Animals Cell Cycle Proteins Cell Differentiation - radiation effects Cell Survival - radiation effects Cell Transformation, Neoplastic Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Disease Models, Animal Epiregulin - metabolism ErbB Receptors - metabolism Female Homeostasis - radiation effects Intestinal Mucosa - metabolism Intestines - cytology Intestines - radiation effects Male Mice Neoplastic Stem Cells - cytology Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Organoids - metabolism Paneth Cells - cytology Paneth Cells - radiation effects Phosphoproteins - deficiency Phosphoproteins - metabolism Protein-Serine-Threonine Kinases - metabolism Radiation, Ionizing Receptors, G-Protein-Coupled - metabolism Regeneration - radiation effects Stem Cells - cytology Stem Cells - metabolism Stem Cells - radiation effects Wnt Signaling Pathway |
| title | Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer |
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