Our body’s 40 trillion cells are subjected to a large number of different forces. For the correct functioning of the organism and to maintain the integrity of the tissues, each cell must measure these forces and react to them, adapting their behavior to the extracellular environment. The impact of physical and mechanical signals in the regulation of cell plasticity and in the tumor transformation process is a rather recent acquisition. Only in the late 1970s did we begin to look at these forces, which had hitherto been neglected in favor of the study of biochemical signals within cells, tissues and organisms. We talk about it with one of the leading experts in Italy, Stefano Piccolo of the Department of Molecular Medicine of the University of Padua and the Foundation Institute of Molecular Oncology Ifom in Milan. «So far we have focused on the intrinsic characteristics of cancer cells but we have understood that it is a perspective that is at least restrictive when not wrong» he tells us «For the cancer seed to germinate the soil must be appropriate. In fact, today we prefer to talk about the cancer ecosystem, in which the cell is only one element among many». Stefano Piccolo is one of the fathers of the so-called cellular mechanotransduction, a phenomenon whereby cells translate the information they receive from the physical and structural characteristics of their microenvironment, their shape and cytoskeletal organization. For his studies, which have led to decisive contributions to the discovery of how this occurs in physiological or pathological conditions, he has received numerous national and international funding, including numerous grants from Airc.
“An important element of the ecosystem is defined by the architecture of the tumor tissue itself,” he says. The revenge of physics and mechanics on biology and chemistry in biomedical research? «Call it what you prefer, physical strength, mechanics, architecture, structural framework: it happens that an element of the microenvironment is triggered by something else that changes the game and which can be inflammation, fibrosis, aging or other more or less permissive ancillary conditions to the appearance of the disease, which in turn will modify the environment to its advantage» he replies «In fact, we must not forget that cancer has its roots in life itself, that to develop it uses all those evolutionary mechanisms that allow us to survive». One cannot help but think of our continuous attempt to replace the normal processes of evolution to quickly adapt everything to our advantage, from when we fight against cell proliferation or against viruses and bacteria to when we edit DNA or try to fight cancer .
Some structural changes in the environment surrounding the cell induce responses inside it which, in turn, reverberate the environment again in a continuum of actions and iterations: «The malignancy of some tumours, which are disseminated throughout the body, depends precisely on the response to these forces, by virtue of which the cells acquire the migratory phenotype giving rise to metastases. Our work aims to stop or reverse this process by aiming at the possibility of regressing overt injuries”.
The development of a tumor is a complex and dynamic process, which does not depend on a single factor, a physical force or a mechanical property such as the stiffness of the substrate. Furthermore, we still don’t know if the chicken or the egg comes first: if the tendency of neoplastic cells to migrate is a response to changed physical properties of the microenvironment, such as deformation or confinement, or if the cell that has already become malignant responds in an altered way to the microenvironment. “We have studied the translation of mechanical stimuli into genetic language, the biochemical language of cells and we have seen that at the basis of this communication there are transcription factors that are also involved in the regulation of cellular function through the maintenance of DNA,” explains Piccolo. “In particular, the role of a gene called YAP is crucial, which induces cell death in the event of excessive damage to the DNA and which can be an Achilles heel that can be exploited”.
«Metastasis as a mechanical disease» is the project coordinated by Stefano Piccolo, financed with the 5 per Mille 2019, one of the eight Airc projects dedicated to the study of metastatic disease. The signatures for the ‘5 per thousand’ intended for the AIRC Foundation translated, at the end of 2022, into over 80 million euros destined for individual research projects and to guarantee continuity to the special programs dedicated to the study of metastases and to oncological research of international avant-garde, to make cancer ever more curable.