A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

Scott Waddell; Yuelin Yao; Paula  Olaizola; Alexander Walker; Ed Jarman; Konstantinos  Gournopanos; Andreea Gradinaru; Ersi Christodoulou; Philippe Gautier; Melissa M  Boerrigter; Massimiliano  Cadamuro; Luca  Fabris; Joost Ph  Drenth; Timothy J. Kendall; Jesus M Banales; Ava Khamseh; Pleasantine Mill; Luke Boulter

doi:10.1126/scitranslmed.abq5930

A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

Scott Waddell, Yuelin Yao, Paula Olaizola, Alexander Walker, Ed Jarman, Konstantinos Gournopanos, Andreea Gradinaru, Ersi Christodoulou, Philippe Gautier, Melissa M Boerrigter, Massimiliano Cadamuro, Luca Fabris, Joost Ph Drenth, Timothy J. Kendall, Jesus M Banales, Ava Khamseh, Pleasantine Mill^*, Luke Boulter^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Original language	English
Journal	Science Translational Medicine
DOIs	https://doi.org/10.1126/scitranslmed.abq5930
Publication status	Published - 13 Sept 2023

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10.1126/scitranslmed.abq5930

Waddell et al Science Translational Medicine_PureAccepted author manuscript, 6.4 MBLicence: Creative Commons: Attribution (CC-BY)
Waddell et al Science Translational Medicine_Pure_SupplementalAccepted author manuscript, 15.2 MBLicence: Creative Commons: Attribution (CC-BY)

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Waddell, S., Yao, Y., Olaizola, P., Walker, A., Jarman, E., Gournopanos, K., Gradinaru, A., Christodoulou, E., Gautier, P., Boerrigter, M. M., Cadamuro, M., Fabris, L., Drenth, J. P., Kendall, T. J., Banales, J. M., Khamseh, A., Mill, P., & Boulter, L. (2023). A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.abq5930

@article{201fed6c10d349c68eeb563fb0bdc682,

title = "A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease",

author = "Scott Waddell and Yuelin Yao and Paula Olaizola and Alexander Walker and Ed Jarman and Konstantinos Gournopanos and Andreea Gradinaru and Ersi Christodoulou and Philippe Gautier and Boerrigter, {Melissa M} and Massimiliano Cadamuro and Luca Fabris and Drenth, {Joost Ph} and Kendall, {Timothy J.} and Banales, {Jesus M} and Ava Khamseh and Pleasantine Mill and Luke Boulter",

note = "Funding Information: S.H.W. is funded by a Chief Scientist Office (CSO) Early post-doctoral fellowship (EPD/22/12). J.M.B. is supported by Spanish Carlos III Health Institute (ISCIII) [(FIS PI18/01075, PI21/00922, and Miguel Servet Programme CPII19/00008) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER)] and CIBERehd (ISCIII), La Caixa Scientific Foundation (HR17-00601), AMMF-the Cholangiocarcinoma Charity (EU/2019/AMMFt/001), PSC Partners US and PSC Supports UK (06119JB), and European Union's Horizon 2020 research and innovation program (grant number 825510, ESCALON). P.O. was supported by a Juan Rod{\'e}s Fellowship (POS_2022_1_0044, IKM_2023_1_0024) from the Spanish Association for the Study of the Liver (AEEH). A.K. was supported by the XDF programme from the University of Edinburgh and Medical Research Council (MC_UU_00009/2). P.M. is funded by an MRC Unit award (MC_UU_00007/14) and ERC Consolidator grant (866355). A Cancer Research UK Fellowship (C52499/A27948) funds L.B. Funding Information: Acknowledgments:W ewouldliketothanktheIGCAdvancedImagingResource,S.Campbell andL.FreyerattheIGCCytometryandSingleCellCorefacility,R.ClarkeattheW ellcome Trust ClinicalResearchFacility(UniversityofEdinburgh),andP .Gautierforbioinformaticssupport. Funding:S.H.W .isfundedbyaChiefScientistOffice(CSO)Earlypost-doctoralfellowship(EPD/ 22/12).J.M.B.issupportedbySpanishCarlosIIIHealthInstitute(ISCIII)[(FISPI18/01075,PI21/ 00922,andMiguelServetProgrammeCPII19/00008)cofinancedby“FondoEuropeode DesarrolloRegional”(FEDER)]andCIBERehd(ISCIII),LaCaixaScientificFoundation(HR17-00601),AMMF–theCholangiocarcinomaCharity(EU/2019/AMMFt/001),PSCPartnersUSand PSC Supports UK (06119JB), and European Union{\textquoteright}s Horizon 2020 research and innovation program(grantnumber825510,ESCAL ON). P .O. wassupportedbyaJuanRod{\'e}sFellowship (POS_2022_1_0044,IKM_2023_1_0024)fromtheSpanishAssociationfortheStudyoftheLiver (AEEH).A.K.wassupportedbytheXDFprogrammefromtheUniversityofEdinburghand MedicalResearchCouncil(MC_UU_00009/2).P .M. isfundedbyanMRCUnitaward (MC_UU_00007/14)andERCConsolidatorgrant(866355).ACancerResearchUKFellowship (C52499/A27948)fundsL.B.Authorcontributions:S.H.W .plannedandperformed experiments,analyzedthedata,anddraftedandeditedthemanuscript.Y .Y .analyzeddataand generatedfiguresforthemanuscript.P .O. designedandperformedexperimentsandanalyzed data.E.J.J.andA.W .analyzedthedata.A.G.andE.C.performedexperimentsforthemanuscript. P .G. analyzeddataandgeneratedfiguresforthemanuscript.K.G.providedtechnicalsupport andperformedtheanimalwork.J.P .H.D., M.M.B.,M.C.,andL.F .providedhumansamplesforthis study.T .J.K. providedclinicalpathologicalsupportandclinicaltissue.J.M.B.provided intellectualinput,tissue,andcells.A.K.pro vided analyticalsupport,supervisedscRNA-seq analysis,andeditedthemanuscript.P .M. andL.B.ledtheproject,designedandcarriedout experiments,analyzedthedata,andwroteandeditedthemanuscript.Competinginterests: T .K. servesasacommitteememberfortheBritishAssociationfortheStudyofLiver.Allother authorsdeclarethattheyhav enocompetinginterests.Dataandmaterialsavailability:All dataassociatedwiththisstudyarepresentinthepaperortheSupplementaryMaterials.RNA-seqdatafromthisstudyareavailablefromDryad(doi:10.5061/dryad.mkkwh7152)andfrom NCBIGEOaccessionGSE145271.Allmaterialsgeneratedaspartofthisstudywillbemade available upon request to the corresponding authors. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2023",

month = sep,

day = "13",

doi = "10.1126/scitranslmed.abq5930",

language = "English",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

}

Waddell, S, Yao, Y, Olaizola, P, Walker, A , Jarman, E, Gournopanos, K, Gradinaru, A, Christodoulou, E, Gautier, P, Boerrigter, MM, Cadamuro, M, Fabris, L, Drenth, JP, Kendall, TJ, Banales, JM, Khamseh, A , Mill, P & Boulter, L 2023, 'A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease', Science Translational Medicine. https://doi.org/10.1126/scitranslmed.abq5930

TY - JOUR

T1 - A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

AU - Waddell, Scott

AU - Yao, Yuelin

AU - Olaizola, Paula

AU - Walker, Alexander

AU - Jarman, Ed

AU - Gournopanos, Konstantinos

AU - Gradinaru, Andreea

AU - Christodoulou, Ersi

AU - Gautier, Philippe

AU - Boerrigter, Melissa M

AU - Cadamuro, Massimiliano

AU - Fabris, Luca

AU - Drenth, Joost Ph

AU - Kendall, Timothy J.

AU - Banales, Jesus M

AU - Khamseh, Ava

AU - Mill, Pleasantine

AU - Boulter, Luke

N1 - Funding Information: S.H.W. is funded by a Chief Scientist Office (CSO) Early post-doctoral fellowship (EPD/22/12). J.M.B. is supported by Spanish Carlos III Health Institute (ISCIII) [(FIS PI18/01075, PI21/00922, and Miguel Servet Programme CPII19/00008) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER)] and CIBERehd (ISCIII), La Caixa Scientific Foundation (HR17-00601), AMMF-the Cholangiocarcinoma Charity (EU/2019/AMMFt/001), PSC Partners US and PSC Supports UK (06119JB), and European Union's Horizon 2020 research and innovation program (grant number 825510, ESCALON). P.O. was supported by a Juan Rodés Fellowship (POS_2022_1_0044, IKM_2023_1_0024) from the Spanish Association for the Study of the Liver (AEEH). A.K. was supported by the XDF programme from the University of Edinburgh and Medical Research Council (MC_UU_00009/2). P.M. is funded by an MRC Unit award (MC_UU_00007/14) and ERC Consolidator grant (866355). A Cancer Research UK Fellowship (C52499/A27948) funds L.B. Funding Information: Acknowledgments:W ewouldliketothanktheIGCAdvancedImagingResource,S.Campbell andL.FreyerattheIGCCytometryandSingleCellCorefacility,R.ClarkeattheW ellcome Trust ClinicalResearchFacility(UniversityofEdinburgh),andP .Gautierforbioinformaticssupport. Funding:S.H.W .isfundedbyaChiefScientistOffice(CSO)Earlypost-doctoralfellowship(EPD/ 22/12).J.M.B.issupportedbySpanishCarlosIIIHealthInstitute(ISCIII)[(FISPI18/01075,PI21/ 00922,andMiguelServetProgrammeCPII19/00008)cofinancedby“FondoEuropeode DesarrolloRegional”(FEDER)]andCIBERehd(ISCIII),LaCaixaScientificFoundation(HR17-00601),AMMF–theCholangiocarcinomaCharity(EU/2019/AMMFt/001),PSCPartnersUSand PSC Supports UK (06119JB), and European Union’s Horizon 2020 research and innovation program(grantnumber825510,ESCAL ON). P .O. wassupportedbyaJuanRodésFellowship (POS_2022_1_0044,IKM_2023_1_0024)fromtheSpanishAssociationfortheStudyoftheLiver (AEEH).A.K.wassupportedbytheXDFprogrammefromtheUniversityofEdinburghand MedicalResearchCouncil(MC_UU_00009/2).P .M. isfundedbyanMRCUnitaward (MC_UU_00007/14)andERCConsolidatorgrant(866355).ACancerResearchUKFellowship (C52499/A27948)fundsL.B.Authorcontributions:S.H.W .plannedandperformed experiments,analyzedthedata,anddraftedandeditedthemanuscript.Y .Y .analyzeddataand generatedfiguresforthemanuscript.P .O. designedandperformedexperimentsandanalyzed data.E.J.J.andA.W .analyzedthedata.A.G.andE.C.performedexperimentsforthemanuscript. P .G. analyzeddataandgeneratedfiguresforthemanuscript.K.G.providedtechnicalsupport andperformedtheanimalwork.J.P .H.D., M.M.B.,M.C.,andL.F .providedhumansamplesforthis study.T .J.K. providedclinicalpathologicalsupportandclinicaltissue.J.M.B.provided intellectualinput,tissue,andcells.A.K.pro vided analyticalsupport,supervisedscRNA-seq analysis,andeditedthemanuscript.P .M. andL.B.ledtheproject,designedandcarriedout experiments,analyzedthedata,andwroteandeditedthemanuscript.Competinginterests: T .K. servesasacommitteememberfortheBritishAssociationfortheStudyofLiver.Allother authorsdeclarethattheyhav enocompetinginterests.Dataandmaterialsavailability:All dataassociatedwiththisstudyarepresentinthepaperortheSupplementaryMaterials.RNA-seqdatafromthisstudyareavailablefromDryad(doi:10.5061/dryad.mkkwh7152)andfrom NCBIGEOaccessionGSE145271.Allmaterialsgeneratedaspartofthisstudywillbemade available upon request to the corresponding authors. Publisher Copyright: Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2023/9/13

Y1 - 2023/9/13

U2 - 10.1126/scitranslmed.abq5930

DO - 10.1126/scitranslmed.abq5930

M3 - Article

SN - 1946-6234

JO - Science Translational Medicine

JF - Science Translational Medicine

ER -

A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

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