Study reveals the architectural design of cancer metastases
01.04.2026
Metastasis is often imagined as something very chaotic: cancer cells breaking away, dispersing, proliferating uncontrollably. The research group from the University of Padua, 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. For this reason, scientists have conducted three-dimensional reconstructions of human tumors and other experimental systems. The study is part of the AIRC “5 per mille” program titled "Metastasis as a mechanical disease," coordinated by Stefano Piccolo, professor of the Department of Molecular Medicine at 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 every living form, has a three-dimensional shape. Embracing the third dimension is not only a technical change of perspective but brings with it a radically new vision of the disease and intervention possibilities that were unthinkable from an exclusively flat perspective. What we have observed is, in the end, simple to imagine. Instead of forming a single dense and round mass, the metastasis grows like a delicate network of connected cellular cords. These cords divide, elongate, branch again, spreading through the tissue like the roots of a plant, expanding in all directions. The result is an open structure, very orderly, with the shape of a thin weave, certainly not a randomly built or compact structure. And this braided cord structure, as the study results 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 manage to reach a distant organ and build a new tumor there? The answer that emerges from this study is that they grow following a real three-dimensional construction plan.
The tumor doesn't 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 type of biological program that, at the beginning of life, helps build tissues and organs. In the embryo, this program is part of the wonder of living. In cancer, that same power is distorted: a developmental program that reignites in the wrong place at the wrong time, used not to create a healthy and nascent organ, but to build a lethal tumor.
The next step was made possible by collaboration with the group led by Professor Massimiliano Pagani at IFOM, always within the “5 per mille” program coordinated by Piccolo.
The research team discovered that this process is coordinated by a group of "foreman" genes, or "architect" genes, of this metastatic "construction site": the ETV genes. These are real molecular switches that activate this same construction program in cancer cells. These genes do not simply make the tumor grow generically "more." Rather, they tell the cells how to organize themselves in space, how to branch out, how to assemble the three-dimensional structure necessary for metastatic growth. And they do not regulate only quantity: they also regulate the structural plan with 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 take on a more compact, solid, closed architecture. Cancer cells can still form at the primary site and spread to other organs, but in most cases, they cannot build actual metastases. They lack the blueprint. They lack the information needed to build the most dangerous form of the disease. Tumors lacking this program remain isolated cells or small blocked lesions; it is the branched ones that give rise to manifest metastases.
This also helps explain a crucial clinical reality: tumors with different architectures behave very differently.
The results collected in the study suggest that some primary breast tumors already carry this dangerous construction plan within them, while others do not. Tumors with a branched architecture are those associated with the ability to metastasize; tumors with a more compact and solid structure resemble non-metastatic tumors: those more easily controllable or curable, because they do not possess the instructions to build metastases. The branching program, already visible in the primary tumor, 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 uncontrolled cell proliferation. It is also a matter of construction. A dangerous tumor has within it a precise program to build itself at a distance. A program that comes from one of the oldest mechanisms of biology: the one that, at the beginning, built us.
The data from the study also reveal a possible weak point in the structure, a possible point of failure: the tumor has not only "stolen" the embryonic program but has also inherited its vulnerabilities.
Scientists 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 humans, to build any branched structure in the body. Blocking FGF hinders metastatic growth while largely leaving the primary tumor intact: under such conditions, cancer cells can remain alive but cannot build the final, disseminated, and distant structure that makes them lethal. About 90 percent of cancer deaths are due to metastases. But FGF might be just the beginning, as many other molecules essential for building an organism could prove to be Achilles' heels of metastases.
“Multi-omic analyses have 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.”
