Conti, SeforaVenturini, ValeriaCañellas Socias, AdriàCortina Duran, CarmeAbenza, Juan F.Stephan-Otto Attolini, CamilleMiddendorp Guerra, EmilyXu, Catherine K.Li, Jia HuiRossetti, LeoneStassi, GiorgioRoca-Cusachs, PereDiz-Muñoz, AlbaRuprecht, VerenaGuck, JochenBatlle Gómez, EduardLabernadie, AnnaTrepat, Xavier2024-08-012024-08-012024Conti 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/s41467-024-47227-22041-1723http://hdl.handle.net/10230/60880Colorectal 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-024-47227-2Biomedical engineeringBiophysicsGastrointestinal cancerinfo:eu-repo/semantics/openAccess