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We thank all the members of the Trepat and Roca-Cusachs lab for support and discussion. We thank Anghara Menendez Montes, Susana Usieto, Monica Purciolas, the core facility for biostatistics at IRB Barcelona and the Cytometry Unit from Scientific and Technological Centers (CCiTUB), Universitat de Barcelona, for technical assistance. We thank Tina Haase for providing HUVEC cells. We thank Srivatsava Viswanadha Venkata Naga Sai for valuable suggestions. Finally, we thank Marija Matejcic, Alice Perucca, Gerardo Ceada, Amy Beedle for their feedback on the manuscript and suggestions. 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.), Fundacio la Marato 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.

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

Publicated to:Nature Communications. 15 (1): 3363- - 2024-04-18 15(1), DOI: 10.1038/s41467-024-47227-2

Authors: Conti, Sefora; Venturini, Valeria; Canellas-Socias, Adria; Cortina, Carme; Abenza, Juan F; Attolini, Camille Stephan-Otto; Guerra, Emily Middendorp; Xu, Catherine K; Li, Jia Hui; Rossetti, Leone; Stassi, Giorgio; Roca-Cusachs, Pere; Diz-Munoz, Alba; Ruprecht, Verena; Guck, Jochen; Batlle, Eduard; Labernadie, Anna; Trepat, Xavier

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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. The mechanical properties of heterogeneous cell populations in colorectal tumors and the relevance to cancer metastasis remain not fully understood. Here, the authors suggest that the variations in malignant phenotypes between LGR5-positive cancer stem cells and LGR5-negative cells could be due to their distinct mechanical phenotypes observed in vitro, determined by the membrane to cortex attachment proteins Ezrin/Radixin/Moesin.

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