Breast cancer: cells become more aggressive due to their 'feel'

Sometimes growing in a difficult environment may not be all bad, because it helps to fortify oneself. This rule appears to be valid, unfortunately, also for the cells that give rise to breast cancer: if at first they are subjected to strong environmental pressure because they are forced to develop in a confined space, over time they may take on more malignant characteristics and above all have greater ease in replicating at a distance, giving rise to metastases. The hypothesis, which is also fascinating for the prospects it opens up on the therapeutic front, emerges from research by experts at the University of Adelaide coordinated by Michael Samuel and published in Science Advances, somehow reveals how much and how there are tumours that manage to grow locally and develop at a distance with ease, while others do not. More importantly, it reveals a role for physics in determining the advantage of certain cell clones. According to the study, the intense mechanical pressure to which tumour cells are subjected at an early stage, while growing compressed in a confined space, may in fact be advantageous for their growth and above all leave a kind of 'imprinting' that makes them stronger in future development.

In order to explain what is happening, it is somehow necessary to go back to a human sense, touch. The breast cancer cells in fact employ precisely the ability to 'use' a specific sensor, precisely that which characterises the sense in humans, to multiply more rapidly and move away, creating distant localisations. In practice, the aggressive behaviour of the cells is maintained even after the pressure stimulus on the cells typical of the early stages of the disease has ceased to exist. These units must in fact develop in confined spaces such as the galactophore ducts (the channels through which breast milk flows). And this pressure would be a kind of educational model that then leads the cells to develop and replicate even at a distance, influencing the progression of the disease. But how does the tactile perception of cells arise? Basically, these neoplastic units are able to detect environmental pressure with the PIEZO1 molecule, which somehow connects the intracellular environment with the external one. Under pressure stimulus PIEZO1 allows calcium ions to flow inside the cell, triggering a series of signals, including a particular cascade of phenomena, called Rho-ROCK, which is a key regulator of cell movement, shape and growth.

According to the research, it is the mechanical pressure on the tumour tissue, and thus on the cells, that drives these pathways. This alone, in laboratory models of breast cancer, showed how the most compressed lesions grew more and, above all, how the tumour cells divided more rapidly. Not only that. With pressure, the aggressiveness and ability of the cells to spread also changes. Finally, it must be said that, when any targeted treatments become available, early diagnosis will be even more important. Tumour cells would in fact have a sort of mechanical 'memory' that would practically maintain the negative effect over time. In practice, therefore, there would be an epigenetic mechanical memory, determined precisely by short-term mechanical forces.

Finally, according to the study, PIEZO1 is more abundant in breast tumours than in normal breast tissue and that the amount of PIEZO1 varies from patient to patient. Not only that, high levels of PIEZO1 are associated with poor patient survival, suggesting that the same pressure-sensing mechanism identified in experimental models is likely to be relevant in human tumours. In short, this opens the way to hope, albeit an experimental pathway: by inhibiting PIEZO1 and/or the Rho-ROCK pathway with tailor-made drugs, compression may not be able to stimulate the tumour's increased aggressiveness. With better disease management. "The discovery of the 'mechanical memory' of breast cancer cells adds a further piece to our knowledge," comments Lucia del Mastro, Professor of Medical Oncology at the University of Genoa. In particular, 'mechanical memory' could be one of the reasons for the greater risk of metastasisation that we observe in larger tumours. Not only that. The data reinforces once again the importance of early diagnosis: tumours discovered when they are smaller could also be biologically less aggressive. Finally, this study opens the way for therapies with new therapeutic targets such as the PIEZO1 sensor and the Rho-Rock pathway'.

This form of epigenetic mechanical memory provides a molecular explanation of how short-term mechanical forces at the cellular level can have long-term consequences on tumour behaviour.