A study by the University of Padua reveals the architectural design of cancer metastases

Metastasis is often imagined as something very chaotic: cancer cells that detach, disperse, proliferate out of control. The research group from the University of Padua, the IOV and the AIRC Institute of Molecular Oncology (IFOM), has shown through the study “A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer” that metastatic breast cancer does not expand randomly, but through an orderly design – almost a biological construction site with its rules and geometry. Scientists have therefore carried out three-dimensional reconstructions of human tumors and other experimental systems. The study is part of the AIRC “5 per mille” program entitled “Metastasis as a mechanical disease”, coordinated by Stefano Piccolo, professor of the Department of Molecular Medicine of the University of Padua and IFOM.
“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 a microscope, histology, or the flat photograph of the disease, has long dominated research, also due to the lack of other technical possibilities,” explains Piccolo. “But cancer, like every organ and like every living form, has a three-dimensional form. Embracing the third dimension is a change of perspective that is not only technical; it brings a radically new vision of the disease and possibilities for intervention that were hitherto unthinkable from an exclusively flat perspective. What we have observed is, after all, simple to imagine. Instead of forming a single, dense, round mass, the metastasis grows into a delicate network of interconnected cellular cords. These cords divide, stretch, branch further, spreading through the tissue like the roots of a plant, expanding in all directions. The result is an open, very orderly structure, with the shape of a thin texture, and certainly not a structure built at random or compact. And this shape of intertwined cords, as the results of the study show, is functional to the success of the metastasis itself”. The question that has always accompanied cancer research is this: how do a few dispersed cancer cells reach a distant organ and build a new tumor? The answer that emerges from this study is that these grow following a real three-dimensional construction plan.
Cancer does not invent anything 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 kind of biological program that, early in life, helps build tissues and organs. In the embryo, this program is part of the wonder of the living. In cancer, that same power is distorted: a developmental program that is rekindled in the wrong place, at the wrong time, used not to create a healthy, nascent organ, but to build a lethal tumor.
The next step was made possible through collaboration with the group led by Professor Massimiliano Pagani at IFOM, again as part of the “5 per thousand” program coordinated by Piccolo.Il research team discovered that this process is coordinated by a group of “master builder” genes, or “architect” genes, of this metastatic “construction site”: the ETV genes. These are real molecular switches that activate, in cancer cells, this same building program. These genes do not just make the tumor grow generically “more”. Rather, they show cells how to organize themselves in space, how to branch, how to assemble the three-dimensional structure necessary for metastatic growth. And they don’t just regulate quantity: they also regulate the structural plan by which cancer generates itself. And this is one of the most important results of the study. When these architect-genes are silenced, tumors do not disappear but lose the ability to grow as branched networks and instead adopt a more compact, more solid, more closed architecture. Cancer cells can still form at the primary site and spread to other organs, but in most cases they fail to build true metastases. They lack the project. They lack the information necessary to build the most dangerous form of the disease. Tumors without this program remain isolated cells or small, blocked lesions; instead, the branched ones give rise to manifest metastases. This also helps explain a crucial clinical reality: tumors with different architectures behave profoundly differently. The results of the study suggest that some primary breast cancers already have this dangerous construction plan, while others do not. Cancers with branched architecture are those associated with the ability to metastasize; Tumors with a more compact and solid structure, on the other hand, resemble non-metastatic tumors: those that are more easily controlled or cured, because they do not possess the instructions to build metastases. The branching program, already visible in the primary tumor, seems to anticipate the identification of 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 an architecture. Metastasis is not just a matter of altered genes or cells proliferating unchecked. It’s also a matter of construction. A dangerous tumor has in itself a precise program to build itself up at a distance. A program that comes from one of the oldest mechanisms in biology: the one that, in the beginning, built us. The data of the study also reveals a possible weak point in the structure, a possible point of failure: the tumor, in fact, has not only “stolen” the embryonic program, but has also inherited its vulnerabilities. Scientists have known for decades which molecular signals are essential for an organ to form. One of these molecules is FGF, or fibroblast growth factor, a molecule that is essential for insects to humans to build any branching structure in the body. Blocking FGF hinders metastatic growth while leaving the primary tumor largely intact: in such conditions, cancer cells can remain alive, but fail to build the final, disseminated, and distant structure that makes them lethal. About 90 percent of cancer deaths are, in fact, due to metastases. But FGF could be just the beginning, as many other molecules essential to building an organism could prove to be the Achilles heels of metastasis.” Multi-omics analyses have revealed that these ‘architect genes’ do not act alone, but activate an entire network of signals of embryonic development”, explains Massimiliano Pagani. “This means that we do not have a single target, but an entire construction logic to dismantle, which multiplies the possibilities of therapeutic intervention.” (aise)