Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis

Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis

Abstract The extracellular matrix (ECM) controls tumour dissemination. We characterise ECM organization in human and mouse tumours, identifying three regions: tumour body, proximal invasive front and distal invasive front. Invasive areas show increased matrix density, fibre thickness, length, and al...

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Main Authors: Oscar Maiques, Marta C. Sallan, Roman Laddach, Pahini Pandya, Adrian Varela, Eva Crosas-Molist, Jaume Barcelo, Olivia Courbot, Yanbo Liu, Vittoria Graziani, Youssef Arafat, Joanne Sewell, Irene Rodriguez-Hernandez, Bruce Fanshawe, Yaiza Jung-Garcia, Paul RC Imbert, Eloise M. Grasset, Jean Albrengues, Maria Santacana, Anna Macià, Jordi Tarragona, Xavier Matias-Guiu, Rosa M. Marti, Sophia Tsoka, Cedric Gaggioli, Jose L. Orgaz, Gilbert O. Fruhwirth, Fredrik Wallberg, Kai Betteridge, Constantino Carlos Reyes-Aldasoro, Syed Haider, Andrejs Braun, Sophia N. Karagiannis, Alberto Elosegui-Artola, Victoria Sanz-Moreno
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56299-7
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Summary:Abstract The extracellular matrix (ECM) controls tumour dissemination. We characterise ECM organization in human and mouse tumours, identifying three regions: tumour body, proximal invasive front and distal invasive front. Invasive areas show increased matrix density, fibre thickness, length, and alignment, with unique radial fibre orientation at the distal invasive front correlating with amoeboid invasive features. Using patient samples and murine models, we find that metastases recapitulate ECM features of the primary tumour. Ex vivo culture of murine cancer cells isolated from the different tumour regions reveals a spatial cytoskeletal and transcriptional memory. Several in vitro models recapitulate the in vivo ECM organisation showing that increased matrix induces 3D confinement supporting Rho-ROCK-Myosin II activity, while radial orientation enhances directional invasion. Spatial transcriptomics identifies a mechano-inflammatory program associated with worse prognosis across multiple tumour types. These findings provide mechanistic insights into how ECM organization shapes local invasion and distant metastasis.
ISSN:2041-1723

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