Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells

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  • dc.contributor.author Conti, Sefora
  • dc.contributor.author Venturini, Valeria
  • dc.contributor.author Cañellas Socias, Adrià
  • dc.contributor.author Cortina Duran, Carme
  • dc.contributor.author Abenza, Juan F.
  • dc.contributor.author Stephan-Otto Attolini, Camille
  • dc.contributor.author Middendorp Guerra, Emily
  • dc.contributor.author Xu, Catherine K.
  • dc.contributor.author Li, Jia Hui
  • dc.contributor.author Rossetti, Leone
  • dc.contributor.author Stassi, Giorgio
  • dc.contributor.author Roca-Cusachs, Pere
  • dc.contributor.author Diz-Muñoz, Alba
  • dc.contributor.author Ruprecht, Verena
  • dc.contributor.author Guck, Jochen
  • dc.contributor.author Batlle Gómez, Eduard
  • dc.contributor.author Labernadie, Anna
  • dc.contributor.author Trepat, Xavier
  • dc.date.accessioned 2024-08-01T13:11:17Z
  • dc.date.available 2024-08-01T13:11:17Z
  • dc.date.issued 2024
  • dc.description.abstract Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing single cell RNA-sequencing (scRNA-seq) expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth.
  • dc.description.sponsorship The work was funded by the Generalitat de Catalunya (AGAUR 2021 SGR 01425 to X.T. and P.R-C., the CERCA Programme, and “ICREA Academia” award to P.R-C., AGAUR SGR-2021-001278 to E.B.); the Spanish Ministry for Science and Innovation MICCINN/FEDER (PID2021-128635NB-I00, MCIN/AEI/ 10.13039/501100011033 and “ERDF-EU A way of making Europe” to X.T., PID2019-110298GB-I00 to P.R-C., Mineco BES-2017-079847 to S.C., PID2020-117011GB-I00 to V.R., PID2020-119917RB-100 to E.B., PID2021-125212OA-I00 to A.L., RYC2020/029736/I to A.L.); the European Research Council (883739 Epifold to X.T., 884623 residualCRC to E.B., 101097753 MechanoSynth to P.R-C.), Fundació la Marató de TV3 (project 201903-30-31-32 to X.T. and E.B. and 201936-30-31 to P.R.-C.); European Commission (H2020-FETPROACT-01-2016-731957 to P.R-C. and X.T.); La Caixa Foundation (LCF/PR/HR20/52400004 and ID 100010434 under the agreement LCF/PR/HR20/52400004 to P.R-C. and X.T., LCF/BQ/PR18/11640001 to A.L.); The European Molecular Biology Laboratory (to A.D-M.); The EMBL Interdisciplinary Postdocs (EIPOD) fellowship under Marie Sklodowska-Curie Actions COFUND and Joachim Herz Foundation Add-on fellowship (to J.H.L); European Union’s Horizon EIC-ESMEA Pathfinder program under grant agreement (101046620 to V.R.); and The Peter and Traudl Engelhorn postdoctoral fellowship to C.K.X; European Union–- NextGenerationEU through the Italian Ministry of University and Research under PNRR–- M4C2-I1.3 Project PE_00000019““HEAL ITALIA (G.S.). IBEC, CRG and IRB are recipients of a Severo Ochoa Award of Excellence from the MINECO.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Conti S, Venturini V, Cañellas-Socias A, Cortina C, Abenza JF, Stephan-Otto Attolini C, et al. Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells. Nat Commun. 2024 Apr 18;15(1):3363. DOI: 10.1038/s41467-024-47227-2
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-47227-2
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/60880
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2024 Apr 18;15(1):3363
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883739
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-128635NB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110298GB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-117011GB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119917RB-100
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-125212OA-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/884623
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101097753
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/731957
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/1010466
  • dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Biomedical engineering
  • dc.subject.keyword Biophysics
  • dc.subject.keyword Gastrointestinal cancer
  • dc.title Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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