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Preventing the tissue’s response to stiffness may be key to slowing the progression of breast tumours

By September 19, 2023July 1st, 2024Research, IBEC

A study led by the BIST centre IBEC demonstrates that laminin, a protein present in breast tissues, prevents the effects of stiffening, protecting cells against tumour growth. While the mechanism has been demonstrated in vitro, persuasive indications suggest its potential applicability in vivo, as observed in patient samples. The work is published in Nature Materials

Cells are capable of translating mechanical changes into biological responses. This process is known as mechanotransduction and plays a fundamental role in the progression of solid tumours, such as breast cancer.

It is well-established that a common mechanical alteration in cancer progression involves tissue hardening. This stiffness is precisely what is detected during self-examinations or breast palpations for potential tumour detection. The stiffness of breast tissue triggers a chain reaction, inducing tension within cells and distorting their nuclei. Ultimately, this nuclear deformation activates genes responsible for controlling cell proliferation, which are closely associated with tumour growth.

A study published in the journal Nature Materials demonstrates a cellular mechanism that could be pivotal in slowing the progression of breast tumours. The results of the study, led by Pere Roca-Cusachs, the principal investigator at the Institute for Bioengineering of Catalonia and the University of Barcelona, indicate that laminin, a protein that provides structure and support to breast tissues, hinders the mechanotransduction process in cells, thereby protecting the nucleus from deformation.

Our findings demonstrate that the presence of laminin mitigates the effects of stiffness, effectively shielding cells from tumour growth. We have showcased this mechanism in vitro, but we believe it holds potential for in vivo application, considering what we have observed in samples from breast cancer patients,” explains Zanetta Kechagia, postdoctoral researcher at IBEC and first author of the study.

Through this mechanism, which we have shown can prevent the invasion of tumour cells, there is potential for the development of more sensitive diagnostic tools or even new therapies for breast cancer. However, further research will be needed to explore these possibilities”, Serra-Hunter, associate professor at the University of Barcelona (UB) and leader of the study, explains.

Breast cells acting non-invasively due to the presence of laminin.

It has already been demonstrated that an increase in tissue stiffness triggers mechanical responses within cells. The most common responses are associated with alterations in the cell’s cytoskeleton, affecting its interaction with the surrounding tissue and facilitating migration. Additionally, this stiffness leads to the activation of the YAP protein, which enters the nucleus and initiates the expression of genes linked to cell proliferation.

To study the mechanotransduction process, the research team cultured breast tissue cells on gels with varying stiffness to mimic both healthy (soft) and malignant (stiff) tissues. They compared the behaviour of the cells on gels coated with laminin to those on gels coated with collagen or fibronectin, which are other cell-supporting proteins that are overproduced in carcinogenic processes.

Thus, the researchers observed that the cells seeded on the laminin-rich gel had a very mild mechanical response to the stiffness of the substrate, compared to those seeded on the gels rich in collagen and fibronectin.

This work is part of the European project MECHANO·CONTROL, receiving funding exceeding seven million euros within the framework of the European FET (Future and Emerging Technologies) projects.

These results represent the culmination of over 6 years of work, during which we received support from the European Commission and collaborated with a team of international institutions, led by IBEC, to better understand how mechanical forces impact breast cancer,” said Daniel Caudepón, IBEC project manager overseeing MECHANO·CONTROL.

This research also includes significant contributions from other institutions participating in MECHANO-CONTROL, including Pablo Sáez and Marino Arroyo from Universitat Politècnica de Catalunya, and Thijs Koorman and Patrick Derksen from University Medical Center Utrecht, The Netherlands.

 

Reference:

Zanetta Kechagia, Pablo Sáez, Manuel Gómez-González, Brenda Canales, Srivatsava Viswanadha, Martín Zamarbide, Ion Andreu, Thijs Koorman, Amy E. M. Beedle, Alberto Elosegui-Artola, Patrick W. B. Derksen, Xavier Trepat, Marino Arroyo & Pere Roca-Cusachs. The laminin–keratin link shields the nucleus from mechanical deformation and signalling. Nature Materials (2023). DOI: 10.1038/s41563-023-01657-3.

Source:
IBEC press release