Study reveals the architectural design of cancer metastases

Metastasis is often imagined as something highly chaotic: cancer cells breaking away, dispersing, proliferating uncontrollably. A new study published in the scientific journal Cell shows instead that metastatic breast cancer does not expand randomly, but follows an orderly pattern, almost like a biological building site governed by precise rules and geometries.

The research group from the University of Padua, IOV and the Istituto AIRC di Oncologia Molecolare (IFOM) showed, through the study A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer, that metastatic cells organise themselves according to a precise three-dimensional plan. To do so, the researchers carried out three-dimensional reconstructions of human tumours and other experimental systems, using advanced imaging and molecular analysis technologies.

The study is part of the AIRC “5 per mille” programme entitled Metastasis as a mechanical disease, coordinated by Stefano Piccolo, lecturer in the Department of Molecular medicine at the University of Padua and at IFOM. Among the authors are researchers affiliated with three Departments of the University: the Department of Surgical, Oncological and Gastroenterological Sciences – DISCOG, the Department of Medicine – DIMED and the Department of Molecular medicine – DMM. Among them is Paolo Angelo Dei Tos, director of DIMED, one of the leading international experts in rare neoplasms and chairman of the European reference network for rare adult solid tumours.

«For decades we have studied cancer in two dimensions. From the pages of books, from the bottom of a Petri dish, from a thin slice of tissue under the microscope, histology, that is, the flat picture of the disease, long dominated research, also because of the lack of other technical possibilities – explains Stefano Piccolo –. But cancer, like every organ and every living form, has a three-dimensional shape. Embracing the third dimension is a shift in perspective that is not only technical; it brings with it a radically new vision of the disease and possibilities for intervention that were previously unthinkable from an exclusively flat perspective.

The three-dimensional reconstructions made it possible to identify a biological process called Metastatic Trabecular Morphogenesis, or metastatic trabecular morphogenesis. Through this mechanism, tumour cells organise themselves into a three-dimensional structure that promotes their expansion in the organs they have reached.

What we observed is, after all, simple to imagine. Instead of forming a single dense, round mass, metastasis grows like a delicate network of cellular cords connected to one another. These cords divide, lengthen, branch again, spreading through the tissue like the roots of a plant, expanding in all directions. The result is an open, highly ordered structure, in the form of a fine mesh, and certainly not one built at random or compact. And this form of intertwined cords, as the study results show, is functional to the success of metastasis itself».

The question that has always accompanied cancer research is this: how do a few scattered tumour cells manage to reach a distant organ and build a new tumour there? The answer emerging from this study is that they grow by following a genuine three-dimensional building plan.

The tumour invents nothing new. Its strength is rooted in the very nature of life. The branching logic followed by these metastatic cells resembles a fundamental process of embryonic development – the same type of biological programme that, at the beginning of life, helps build tissues and organs. In the embryo, this programme is part of the wonder of living things. In cancer, that same power is distorted: a developmental programme that switches back on in the wrong place, at the wrong time, used not to create a healthy, emerging organ, but to build a lethal tumour.

The next step was made possible thanks to collaboration with the group led by Professor Massimiliano Pagani at IFOM, again within the framework of the “5 per mille” programme coordinated by Stefano Piccolo.

The research team discovered that this process is coordinated by a group of “master builder” genes, or “architect” genes, of this metastatic “building site”: the ETV1, ETV4 and ETV5 factors. These are true molecular switches that activate this same building programme in tumour cells. These genes do not merely make the tumour grow generically “more”. Rather, they tell the cells how to organise themselves in space, how to branch, how to assemble the three-dimensional structure needed for metastatic growth. And they regulate not only quantity: they also regulate the structural plan through which cancer generates itself.

And this is one of the study’s most important findings. When these architect genes are silenced, tumours do not disappear but lose the ability to grow as branched networks and instead assume a more compact, more solid, more closed architecture. Tumour cells may still form at the primary site and spread to other organs, but in most cases they are unable to build true metastases. They lack the blueprint. They lack the information needed to construct the most dangerous form of the disease. Tumours deprived of this programme remain isolated cells or small arrested lesions; by contrast, it is the branched ones that give rise to overt metastases.

This also helps explain a crucial clinical reality: tumours with different architectures behave in profoundly different ways. The results gathered in the study suggest that some primary breast tumours already carry this dangerous building plan within them, whereas others do not. Tumours with a branched architecture are those associated with the ability to metastasise; tumours with a more compact and solid structure instead resemble non-metastatic tumours: those more easily controlled or cured, because they do not possess the instructions needed to build metastases. The branching programme, already visible in the primary tumour, seems to identify in advance the lesions destined to spread.

This changes the way we look at cancer. The data obtained in this study suggest that cancer must also be understood as architecture. Metastasis is not only a matter of altered genes or cells proliferating without restraint. It is also a matter of construction. A dangerous tumour contains within itself a precise programme for building itself at a distance. A programme that comes from one of the oldest mechanisms in biology: the one that, in the beginning, built us.

The study data also reveal a possible weak point in the structure, a possible breaking point: the tumour has not only “stolen” the embryonic programme, but has also inherited its vulnerabilities.

Researchers have known for decades which molecular signals are indispensable for an organ to form. One of these molecules is FGF, or fibroblast growth factor, an essential molecule, from insects to human beings, for building any branched structure in the body. Blocking FGF hinders metastatic growth while leaving the primary tumour largely intact: in such conditions tumour cells may remain alive, but they are unable to build the final, disseminated and distant structure that makes them lethal. Indeed, around 90 per cent of cancer deaths are due to metastases. But FGF may be only the beginning, since many other molecules indispensable for building an organism could prove to be just as many Achilles heels of metastases.

«Multi-omics analyses revealed that these “architect genes” do not act alone, but activate an entire network of embryonic development signals – explains Massimiliano Pagani –. This means that we do not have just one target, but an entire construction logic to dismantle, and this multiplies the possibilities for therapeutic intervention».

The identification of metastatic trabecular morphogenesis and its molecular regulators therefore opens up important prospects both for the development of targeted therapies, capable of interfering with the three-dimensional programme of metastasis, and for the identification of personalised treatments based on the biological and architectural characteristics of each tumour.