ADAM17, short for a disintegrin and metalloprotease 17, is also known as tumor necrosis factor-converting enzyme, or TACE. Its defining feature is its ability to shed membrane-bound proteins: it cleaves the extracellular portions of molecules anchored in the cell membrane, releasing them as soluble signaling factors. Among its best-known substrates are the precursors of epidermal growth factor receptor ligands, such as heparin-binding EGF-like growth factor, whose release activates EGFR signaling, a pathway central to cell proliferation and survival. ADAM17 also processes the interleukin-6 receptor, enabling IL-6 trans-signaling, a mechanism that amplifies inflammatory communication between cells. Through these activities, ADAM17 sits at the junction of inflammation and cancer biology, which is why it has been extensively studied in human breast cancer and other malignancies.

What has been missing, the researchers note, is any systematic characterization of ADAM17 signaling in veterinary pathophysiology. Canine mammary tumors share striking biological similarities with human breast cancer, including hormone dependence, histopathological diversity, and a propensity for metastatic spread, yet treatment options for affected dogs remain limited, often revolving around surgery and chemotherapy. The team, led by André Luz and Marina Badenes, with collaborators at NOVA University Lisbon and Lusófona University, set out to determine whether ADAM17 plays a functional role in these tumors and whether modulating the pathway could alter cancer-relevant behaviors.

The first question was clinical: is ADAM17 expressed differently in tumors compared with healthy tissue? The researchers compared ADAM17 mRNA levels in canine mammary carcinoma tissues against normal mammary gland samples. The result was clear. ADAM17 expression was significantly elevated in carcinomas of histopathological grade II or higher relative to normal controls. Because higher histopathological grade reflects greater cellular atypia and more aggressive biological behavior, the finding suggests that ADAM17 upregulation accompanies tumor progression. The authors further suggest that its expression may be associated with tumor progression and dissemination, although supplementary analyses across individual clinical and histopathological parameters, including breed, tumor multiplicity, nodal involvement, distant metastasis, tumor size, necrosis, ulceration, and mitotic activity, did not reveal statistically significant differences for those individual variables.

To probe function rather than mere correlation, the team turned to two established canine mammary tumor cell lines, FR37-CMT and FR10-CMT. Their strategy was pharmacological: stimulate the ADAM17 pathway, inhibit it, and observe what happens to key cancer-related processes. Stimulation was achieved with lipopolysaccharide, a bacterial endotoxin that provokes inflammatory signaling, and with phorbol-12-myristate-13-acetate, or PMA, a potent activator of protein kinase C that is known to trigger ADAM17 activation. Inhibition was pursued with several complementary agents, including batimastat (BB-94), a broad-spectrum metalloprotease inhibitor; GI254023X, which preferentially targets the related protease ADAM10; KP457 and MEDI3622, more selective ADAM17 inhibitors, the latter being an antibody-based inhibitor; and appropriate solvent controls.

The first biological outputs examined were cell viability, apoptosis, and the response to doxorubicin, a mainstay chemotherapeutic drug. Here the results were largely negative, and that in itself is informative. ADAM17 did not appear to play a major role in FR37-CMT cell viability or apoptosis under basal conditions, nor did modulating the pathway change the cytotoxic effectiveness of doxorubicin. In other words, ADAM17 does not seem to be a general survival factor for these tumor cells, and blocking it would not be expected to sensitize them to this particular chemotherapy agent. The team also examined epithelial-to-mesenchymal transition, the developmental program by which epithelial cancer cells acquire invasive, mesenchymal characteristics, and again found no major role for ADAM17 in the FR37-CMT model.

The decisive result came from a different assay: cell motility. Using scratch wound migration assays, in which a confluent cell monolayer is wounded and the rate at which cells close the gap is measured over time points of 4, 8, and 24 hours, the researchers found that activating the ADAM17 pathway enhanced the migration of both FR37-CMT and FR10-CMT cells. PMA stimulation accelerated the recovery of the scratch, and this effect could be blunted by ADAM17-targeted inhibitors. Conversely, inhibiting ADAM17 activity with BB-94, KP457, or MEDI3622 reduced the rate at which cells repopulated the wound, with the selective inhibitors providing mechanistic confirmation that the effect was attributable to ADAM17 rather than to off-target actions of the broader metalloprotease blockade. GI254023X, the ADAM10-preferring inhibitor, contributed additional context by implicating the closely related ADAM10 pathway in motility as well, suggesting a family-level contribution to cell movement in these tumors.

Why does motility matter? Metastasis, the process that makes cancer lethal, begins with local invasion: tumor cells must detach, migrate through surrounding tissue, enter blood or lymphatic vessels, and seed distant organs. A cell’s migratory capacity is therefore a direct functional readout of its metastatic potential. The finding that ADAM17 promotes migration, without appreciably affecting viability or chemotherapy response, refines the picture of what this enzyme does in canine mammary tumors. It is not a driver of tumor cell survival but a facilitator of movement, consistent with its known biology as a sheddase that releases factors enabling cells to remodel their surroundings and respond to motility cues. The supplementary data also showed that amphiregulin secretion by FR37-CMT cells was not increased by pathway activation, hinting that the motility effect may be mediated by other ADAM17 substrates or downstream pathways yet to be pinned down.

The translational implication is straightforward and, for veterinary oncology, potentially significant. If ADAM17 activity drives the migratory behavior of mammary tumor cells, then pharmacological inhibition of ADAM17 could represent a promising strategy to limit the metastatic spread of mammary cancer in dogs, as the authors conclude. This would position an ADAM17 inhibitor not as a cytotoxic drug that kills tumor cells, but as an anti-metastatic agent that restrains their ability to move and invade, an approach that could complement surgery and existing chemotherapy. The availability of selective inhibitors, including the antibody-based MEDI3622 tested in this study, provides a starting point for such a strategy, although the leap from cell culture dishes to canine patients will require further validation, including studies in primary tumor models and ultimately clinical trials.

The study also carries broader resonance beyond veterinary medicine. Because canine mammary tumors are widely regarded as a comparative model for human breast cancer, defining the role of ADAM17 in dogs may illuminate aspects of the enzyme’s behavior that are difficult to dissect in human clinical material. The work, conducted with samples collected in a clinical diagnostic context and approved by the local animal ethics committee, was supported by institutional and Portuguese national science funding, including the Foundation for Science and Technology. For now, the message is a measured one: a well-known human cancer protease has been shown to be upregulated in aggressive canine mammary carcinomas and to promote tumor cell motility, opening a concrete, testable avenue for keeping metastasis at bay in man’s best friend.

Subject of Research: The role of the ADAM17 protease pathway in canine mammary tumor cell migration and metastasis

Article Title: ADAM17 pathway promotes canine mammary tumor cell migration

Article References: Luz, A., Santos, J., Catarino, J., Sousa, C., Fonseca, J., Campos, S., Alves, M., Baptista, P. V., Faísca, P., Fernandes, A. R., & Badenes, M. (2026). ADAM17 pathway promotes canine mammary tumor cell migration. BMC Cancer. https://doi.org/10.1186/s12885-026-16984-2

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16984-2

Keywords: ADAM17, canine mammary tumor, cell migration, metastasis, veterinary oncology, EGFR, IL-6 trans-signaling, metalloprotease inhibitors, EMT, doxorubicin, breast cancer, cell motility

The study, led by Philipp Radler in the laboratory of Christa Schleper at the University of Vienna and published in the journal Nature, provides the first direct observations of Asgard archaeal motility. These organisms are tiny; each cell has a volume roughly a thousand times smaller than that of a human cell. Yet the recordings show them undergoing dramatic transformations of shape on a minute-by-minute basis, extending thin appendages that can reach up to twenty times the length of the cell body, retracting them again, and using them to actively explore their surroundings. The behavior is strikingly reminiscent of the amoeboid movement seen in far more sophisticated cells, including human immune cells patrolling tissue.

Why does this matter so much? Asgard archaea occupy a central position in current models of eukaryogenesis, the process by which the first complex cells emerged roughly two billion years ago. The prevailing scientific framework holds that a eukaryotic ancestor arose from a symbiotic fusion between a bacterium and an archaeal lineage ancestral to today’s Asgard archaea. In that scenario, the bacterium eventually became the mitochondrion, the energy-producing organelle that powers virtually every complex cell on Earth. Asgard archaea are therefore not merely an interesting branch of the microbial tree; they are the closest available window into the cellular world from which our own lineage was born.

Until very recently, that window was almost entirely opaque. The first Asgard archaea were only brought into culture in 2020 and 2023, one at the JAMSTEC Institute in Japan and another in Schleper’s laboratory in Vienna, and both Japanese teams are co-authors on the new study. Before those milestones, essentially everything scientists knew about the group came from DNA sequencing of environmental samples or from electron microscopy of fixed cells. Those static images were already tantalizing: they showed a round cell body surrounded by a halo of fine, branching projections. But a fixed image cannot reveal whether a cell is extending, retracting, or moving, and so the functional significance of these elaborate shapes remained a matter of speculation.

The Vienna team closed that gap with a technically demanding approach. Asgard archaea are anaerobes, organisms that cannot tolerate oxygen, so the researchers placed the cells in an oxygen-free environment and filmed them alive under the microscope. They worked with two strains: a Lokiarchaeon cultivated in Vienna and a Heimdallarchaeon cultivated in Japan. Both organisms displayed the same remarkable repertoire of behaviors, drastically reshaping themselves every minute and deploying their thin, dynamic appendages to attach to surfaces and probe them. The crawling motion they use had not previously been described in any microbe, and its closest parallels lie in the motility of complex eukaryotic cells.

The mechanistic story behind the movement is equally significant. When the team applied actin inhibitors to the cultures, the dynamic behaviors were suppressed. Actin is one of the fundamental components of the cytoskeleton, the internal scaffolding that gives cells their shape, drives their internal transport, and powers their movement. In eukaryotes, an actin-based cytoskeleton underlies everything from muscle contraction to the crawling of immune cells through tissue. Finding that the motility of Asgard archaea likewise depends on actin suggests that a functional actin cytoskeleton, with clear parallels to the one operating in human cells, was already in place in the archaeal lineage long before the first eukaryote existed.

The international collaboration behind the study included, alongside the Japanese microbiologists, researchers from the Institute of Science and Technology Austria and the Helmholtz Centre for Infection Research in Braunschweig, Germany. Their combined expertise in cultivation, microscopy and cell biology was essential to a result that no single laboratory could have achieved alone. Culturing Asgard archaea remains extraordinarily difficult; the organisms grow slowly, in strict anaerobic conditions, and only a handful of laboratories worldwide have managed it. Every live-cell observation therefore represents years of methodological groundwork.

From an evolutionary standpoint, the discovery opens a genuinely new perspective on the deep history of cellular innovation. Complex cell motility may have far older origins than previously assumed, predating the emergence of eukaryotes themselves. If the ancestor of Asgard archaea already possessed the machinery for shape change, surface attachment and crawling, then some of the cellular capabilities once thought to be eukaryotic inventions may instead have been inherited from their archaeal partner. Such capabilities could even have played a role in the ancient symbiosis from which mitochondria later emerged, potentially facilitating the physical interactions between the archaeal host and its bacterial partner that set complex life in motion.

The findings also carry practical implications that extend well beyond evolutionary theory. Because the actin cytoskeleton governs shape changes and motility in human cells, understanding a simpler, archaeal version of the same machinery offers a comparative framework for dissecting how this fundamental system works. Insights gained from organisms that sit at the evolutionary boundary between prokaryotes and eukaryotes can illuminate which features of the eukaryotic cytoskeleton are ancient inheritances and which are later refinements. In this sense, the humble Asgard archaea, invisible to the naked eye and difficult to culture, may help explain processes that are central to human biology, including immune cell migration and cellular architecture.

Perhaps the most consequential aspect of the study is methodological. Oxygen-free live-cell microscopy of Asgard archaea now makes it possible, for the first time, to test models of the origin of complex life against empirical observation rather than inference from genomes and static images. Hypotheses about how the first eukaryotes moved, attached to surfaces, and interacted with partner cells can now be confronted with real footage of their closest living relatives in action. What has emerged from those first recordings, dynamic protrusions, actin-dependent crawling and a fluidity of form once thought to belong exclusively to complex cells, suggests that the road to eukaryotic life may have been paved with cellular behaviors far older and far more sophisticated than anyone had imagined.

Subject of Research: Crawling motility and actin-based cytoskeleton dynamics in Asgard archaea and their implications for eukaryogenesis

Article Title: Unexpected dynamics of ancient microbes discovered

Article References: Unexpected dynamics of ancient microbes discovered. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: Asgard archaea, Lokiarchaeon, Heimdallarchaeon, eukaryogenesis, actin cytoskeleton, cell motility, crawling motility, live-cell microscopy, mitochondria, evolution, University of Vienna, Nature

The findings, published in Science Advances, address a central question in cell biology: how do molecular structures operating at microscopic scales produce coordinated changes across an entire cell? Living cells contain thousands of interacting molecules, making it difficult to determine which processes are essential and which are secondary. To isolate the underlying mechanics, the researchers created cell-sized liposomes, spherical membrane compartments that resemble primitive cells but lack the complex internal machinery of biological organisms.

Inside these liposomes, the team introduced purified components of the actomyosin cytoskeleton. Actin is a protein that polymerizes into filaments, while myosin motor proteins use chemical energy to slide along those filaments and generate contractile forces. In living cells, actomyosin networks help control movement, division, adhesion, and mechanical organization. By reconstructing the network from selected components, the researchers could observe how molecular-scale forces deform a membrane without interference from signaling pathways, organelles, or other cellular systems.

The experiments focused on membrane blebbing, a process in which the cell membrane briefly detaches from the underlying cortex and expands outward as a rounded, bubble-like protrusion. Blebs are involved in several forms of cell movement and can appear at the front or rear of migrating cells. They are also associated with cell division, programmed cell death, and changes in tissue architecture. Although blebs are familiar features of living cells, their formation is governed by a complicated combination of membrane tension, cortical contractility, adhesion, and fluid movement.

When the artificial cells were subjected to a specific physical manipulation, the actomyosin network generated a bleb that expanded in a consistent direction. The liposomes consequently developed a distinct asymmetry, with one region behaving differently from the opposite side. This result indicates that front-rear polarity does not necessarily require a pre-existing biochemical signal or an internal molecular compass. Instead, mechanical stresses within the cytoskeletal network can be sufficient to break the symmetry of an initially uniform cell-like system.

The researchers combined microscopy with large-scale computer simulations and theoretical analysis to connect the behavior of individual actin filaments and myosin motors to changes occurring across the entire liposome. The simulations showed how local contractions can redistribute mechanical stress, alter membrane attachment, and create conditions favorable for bleb formation. Once a protrusion appeared, changes in membrane tension and cytoskeletal organization helped stabilize and enlarge it, allowing a local event to become a cell-scale transformation.

This distinction between local and global mechanisms is important because membrane blebs can arise through more than one physical route. In some cases, contraction of the actomyosin cortex increases internal pressure and forces the membrane outward. In others, a local weakening of the connection between the membrane and cortex allows the membrane to balloon into the surrounding space. By reconstructing the system with controlled ingredients, the researchers were able to distinguish these mechanisms and examine how they interact during bleb formation and symmetry breaking.

“By reconstructing membrane morphogenesis from purified proteins, we showed that local interactions within the actin cytoskeleton are sufficient to generate large-scale changes in cell shape,” Miyazaki said. The result does not mean that biochemical signaling is unimportant in living organisms. Rather, it reveals that signaling may act by regulating a physical system whose basic capacity for shape change is already embedded in the properties of the cytoskeleton, membrane, and surrounding fluid.

The artificial-cell platform could become a useful tool for investigating how cells move, divide, and organize themselves during development. Because the system is quantitatively controllable, researchers can vary protein concentrations, membrane composition, network architecture, and mechanical constraints one factor at a time. The same approach could help identify the minimal ingredients required for other cellular behaviors, including force sensing, directed movement, and dynamic remodeling of internal structures.

The work also contributes to the long-term goal of building autonomous artificial cells. Future versions could incorporate molecular sensors, energy-generating reactions, or programmable biochemical circuits, allowing them to respond to their surroundings or perform specific tasks. Potential applications include drug delivery, regenerative medicine, synthetic biology, and the manufacture of biological compounds. For now, the study provides a fundamental lesson: some of the complexity associated with living cells can emerge from the physics of interacting molecules, even before sophisticated biological signaling networks are added.

Subject of Research: Not applicable

Article Title: Reconstitution of actomyosin networks in cell-sized liposomes dissects distinct mechanisms of membrane blebbing and symmetry breaking

Web References: https://doi.org/10.1126/sciadv.aed8818

References: Science Advances, DOI: 10.1126/sciadv.aed8818

Image Credits: RIKEN

Keywords: artificial cells, actomyosin networks, actin cytoskeleton, myosin, membrane blebbing, cell morphogenesis, symmetry breaking, cell polarity, liposomes, synthetic biology, cellular mechanics, RIKEN