Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis
Maiques, O., Sallan, M. C., Laddach, R. , Pandya, P., Varela, A., Crosas-Molist, E., Barcelo, J., Courbot, O., Liu, Y., Graziani, V., Arafat, Y., Sewell, J., Rodriguez-Hernandez, I., Fanshawe, B., Jung-Garcia, Y., Imbert, P. R. C., Grasset, E. M., Albrengues, J., Santacana, M., Macià, A., Tarragona, J., Matias-Guiu, X., Marti, R. M., Tsoka, S., Gaggioli, C., Orgaz, J. L., Fruhwirth, G. O., Wallberg, F., Betteridge, K., Reyes-Aldasoro, C. C. 
ORCID: 0000-0002-9466-2018, Haider, S., Braun, A., Karagiannis, S. N., Elosegui-Artola, A. & Sanz-Moreno, V. (2025).
Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis.
Nature Communications, 16(1),
article number 1394.
doi: 10.1038/s41467-025-56299-7
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.
| Publication Type: | Article |
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| Additional Information: | This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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. |
| Publisher Keywords: | Cancer microenvironment, Myosin |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Departments: | School of Science & Technology School of Science & Technology > Computer Science |
| SWORD Depositor: |
Available under License Creative Commons Attribution Non-commercial No Derivatives.
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