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

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 and Victoria Sanz-Moreno ()
Additional contact information
Oscar Maiques: Chester Beatty Laboratories
Marta C. Sallan: Chester Beatty Laboratories
Roman Laddach: King’s College London
Pahini Pandya: Guy’s Campus
Adrian Varela: Chester Beatty Laboratories
Eva Crosas-Molist: Chester Beatty Laboratories
Jaume Barcelo: Chester Beatty Laboratories
Olivia Courbot: The Francis Crick Institute
Yanbo Liu: Chester Beatty Laboratories
Vittoria Graziani: Chester Beatty Laboratories
Youssef Arafat: City St George’s, University of London
Joanne Sewell: Charterhouse Square
Irene Rodriguez-Hernandez: Charterhouse Square
Bruce Fanshawe: Guy’s Campus
Yaiza Jung-Garcia: Chester Beatty Laboratories
Paul RC Imbert: Charterhouse Square
Eloise M. Grasset: Nice (IRCAN)
Jean Albrengues: Nice (IRCAN)
Maria Santacana: CIBERONC
Anna Macià: University of Lleida
Jordi Tarragona: CIBERONC
Xavier Matias-Guiu: CIBERONC
Rosa M. Marti: IRB Lleida
Sophia Tsoka: Bush House
Cedric Gaggioli: Nice (IRCAN)
Jose L. Orgaz: Charterhouse Square
Gilbert O. Fruhwirth: King’s College London
Fredrik Wallberg: 84 Wood Ln
Kai Betteridge: Chester Beatty Laboratories
Constantino Carlos Reyes-Aldasoro: City St George’s, University of London
Syed Haider: Chester Beatty Laboratories
Andrejs Braun: Charterhouse Square
Sophia N. Karagiannis: King’s College London
Alberto Elosegui-Artola: City St George’s, University of London
Victoria Sanz-Moreno: Chester Beatty Laboratories

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56299-7

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