ADAM17 Enzyme Drives Migration in Canine Mammary Tumor Cells, Study Finds

A molecular scissor long implicated in human cancer has now been caught in the act in dogs. In a study published in BMC Cancer, a Portuguese research team reports that ADAM17, an enzyme known for clipping proteins off cell surfaces, is significantly upregulated in canine mammary carcinomas and appears to fuel the motility of tumor cells in laboratory models. The finding, drawn from tumor tissue comparisons and experiments on two canine mammary tumor cell lines, points toward a potential anti-metastatic strategy for one of the most common and clinically challenging cancers in female dogs.

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