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

Sefora Conti, Valeria Venturini, Adrià Cañellas-Socias, Carme Cortina, Juan F. Abenza, Camille Stephan-Otto Attolini, Emily Middendorp Guerra, Catherine K. Xu, Jia Hui Li, Leone Rossetti, Giorgio Stassi, Pere Roca-Cusachs, Alba Diz-Muñoz, Verena Ruprecht, Jochen Guck, Eduard Batlle (), Anna Labernadie () and Xavier Trepat ()
Additional contact information
Sefora Conti: The Barcelona Institute for Science and Technology (BIST)
Valeria Venturini: The Barcelona Institute for Science and Technology (BIST)
Adrià Cañellas-Socias: Barcelona Institute of Science and Technology (BIST)
Carme Cortina: Barcelona Institute of Science and Technology (BIST)
Juan F. Abenza: The Barcelona Institute for Science and Technology (BIST)
Camille Stephan-Otto Attolini: Barcelona Institute of Science and Technology (BIST)
Emily Middendorp Guerra: Barcelona Institute of Science and Technology (BIST)
Catherine K. Xu: Max Planck Institute for the Science of Light
Jia Hui Li: European Molecular Biology Laboratory (EMBL)
Leone Rossetti: The Barcelona Institute for Science and Technology (BIST)
Giorgio Stassi: University of Palermo
Pere Roca-Cusachs: The Barcelona Institute for Science and Technology (BIST)
Alba Diz-Muñoz: European Molecular Biology Laboratory (EMBL)
Verena Ruprecht: The Barcelona Institute for Science and Technology (BIST)
Jochen Guck: Max Planck Institute for the Science of Light
Eduard Batlle: Barcelona Institute of Science and Technology (BIST)
Anna Labernadie: The Barcelona Institute for Science and Technology (BIST)
Xavier Trepat: The Barcelona Institute for Science and Technology (BIST)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47227-2

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