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 research, led by Anna Biedritzky and Michael Koeppen at University Hospital of Tuebingen in Germany, focused on a membrane-bound enzyme called ADAM17, short for A Disintegrin and Metalloproteinase 17. This protease is known to cleave, or shed, the outer portions of a wide range of molecules sitting on the cell surface, including adhesion proteins and cytokine receptors. By snipping these molecules, ADAM17 can fundamentally change how immune cells interact with blood vessels and how inflammatory signals propagate through tissue. What remained poorly understood was how much of the lung damage in ARDS could be attributed specifically to the version of ADAM17 produced by endothelial cells, the thin layer of cells lining the pulmonary microvasculature.

To answer this question, the team engineered mice in which the ADAM17 gene could be selectively deleted in endothelial cells using the Cre/loxP system, crossing mice carrying loxP-flanked ADAM17 alleles with Tie2-Cre driver animals. When these knockout mice and their normal littermates inhaled lipopolysaccharide, a bacterial endotoxin that triggers acute lung inflammation, the difference was striking. Three hours after exposure, total lung ADAM17 messenger RNA in the knockout animals was reduced by 77.5 percent compared with controls, demonstrating that endothelial cells are the dominant source of this protease in the inflamed lung. Flow cytometry confirmed that ADAM17 surface expression dropped on pulmonary endothelial cells while remaining intact on neutrophils and platelets, validating the specificity of the genetic deletion.

The most dramatic consequences appeared at the endothelial barrier itself. In control mice, LPS exposure caused the characteristic hallmarks of ARDS-like injury: thickening of the alveolar septa, gaps between endothelial cells, and protein-rich fluid pouring into the airspaces. In the knockout mice, lung architecture was substantially preserved. The researchers traced this protection to the maintenance of junctional integrity. Surface expression of JAM-A, a junctional adhesion molecule that redistributes during inflammation to permit leukocyte passage, was markedly altered in the absence of endothelial ADAM17. Crucially, the tight junction proteins ZO-1, occludin, and claudin-5, along with the adherens junction protein VE-cadherin, were all preserved at higher levels in the knockout animals, both in vivo and in cultured human endothelial and epithelial cells treated with ADAM17 inhibitors.

Functional measurements confirmed what the microscopy suggested. Using the Evans blue extravasation assay, in which a dye bound to albumin leaks out of vessels only when the barrier fails, the team showed that knockout lungs accumulated significantly less dye six hours after LPS challenge, the known peak of vascular leakage in this model. Total protein in bronchoalveolar lavage fluid, an indirect indicator of alveolar-capillary permeability, was also significantly lower in the knockout group. According to the authors, this represents the first direct demonstration of reduced Evans blue extravasation in this endothelial-specific ADAM17 knockout model, providing functional confirmation of a barrier-protective phenotype that earlier work had inferred mainly from histology and lavage protein measurements.

The study also resolved a long-standing question about where neutrophils get stuck when ADAM17 is missing. Rather than simply counting cells in the whole lung, the researchers used a compartment-specific flow cytometry approach, tagging neutrophils still inside the pulmonary vasculature with an intravenously injected antibody before tissue collection. This allowed them to distinguish intravascular, endothelial-adherent, interstitial, and intra-alveolar neutrophils. The results were revealing: knockout mice had similar numbers of circulating neutrophils as controls, but significantly more neutrophils retained at the endothelial surface and significantly fewer in the interstitium and alveolar space. The retained neutrophils showed elevated surface expression of the adhesion molecules CD162, also known as PSGL-1, and CD49d, an integrin subunit, consistent with a failure to complete the transmigration program.

Complementary experiments in a Transwell system, in which human neutrophils migrate across an endothelial-epithelial barrier along a chemotactic gradient of fMLP, reinforced this interpretation. Pharmacological inhibition of ADAM17 with TAPI-1, or dual inhibition of ADAM17 and ADAM10 with GW280264X, significantly reduced neutrophil transmigration, attenuated myeloperoxidase release, and lowered expression of the transmigration-associated molecules CD11b and JAM-A on the cells that did cross. Together, the in vivo and in vitro data suggest that endothelial ADAM17 does not control the initial adhesion of neutrophils to the vessel wall but rather their passage through it, coordinating shedding events that permit immune cells to squeeze between junctional complexes.

Beyond the physical barrier, the study uncovered a selective signaling role for the endothelial protease. Gene expression analysis three hours after LPS inhalation showed that deletion of endothelial ADAM17 selectively dampened two proinflammatory cascades: the TNF receptor 1 pathway, with reduced downstream NF-kappaB, JNK, TRADD, and CREB transcripts, and the interleukin-6 receptor pathway, with reduced JAK1 and STAT3 expression. In contrast, the TLR4 pathway, the primary sensor for bacterial endotoxin, was activated to the same degree in knockout and control mice, and immunostaining located TLR4 on endothelial cells, epithelial cells, and infiltrating neutrophils in both genotypes. The maturation and trafficking machinery for ADAM17 itself, involving iRhom2, AT1R, and iTAP, was likewise unaffected, indicating that the enzyme’s influence operates through its shedding substrates rather than through its own regulation.

The downstream consequences for the alveolar inflammatory milieu were substantial. Bronchoalveolar lavage fluid from knockout mice contained significantly less TNF-alpha, less soluble CD62L, less myeloperoxidase, and less neutrophil elastase, while levels of the anti-inflammatory cytokine IL-10 were higher, indicating a shift toward a resolving, less tissue-destructive environment. Pharmacological inhibition largely reproduced the genetic phenotype: TAPI-1 reduced interstitial neutrophil accumulation, GW280264X reduced both interstitial and alveolar accumulation, and both inhibitors preserved VE-cadherin expression, reduced chemokine CXCL2/3 release, and limited Evans blue leakage. Dual inhibition even caused neutrophils to pile up at the endothelium, mirroring the genetic knockout and pointing to cooperative roles for ADAM17 and ADAM10 in the transmigration cascade.

The authors are careful to note the translational caveats. In this study, inhibitors were given one hour before the LPS challenge, a standard target-validation design, so whether ADAM17 blockade helps after lung injury has already begun remains to be tested. Because ADAM17 has a broad substrate repertoire with physiological functions throughout the body, the authors suggest that future therapies may need to be temporally restricted, endothelial-targeted, locally delivered, or substrate-selective to minimize systemic side effects. Even with these limitations, the convergence of endothelial-specific genetic deletion and differential pharmacological inhibition makes a compelling case that ADAM17 on the pulmonary endothelium acts as a central inflammatory amplifier in acute lung injury, coordinating neutrophil trafficking, junctional destabilization, vascular leakage, and cytokine signaling. For a syndrome with mortality approaching forty percent and few options beyond supportive care, a druggable molecular chokepoint on the vessel wall is exactly the kind of target the field has been searching for.

Subject of Research: The role of endothelial ADAM17 in neutrophil migration and microvascular permeability during acute lung inflammation

Article Title: Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation

Article References: Biedritzky, A., Kleinmaier, C., Fuhr, A., Herrmann, L. M., Ngamsri, K.-C., Konrad, F., & Koeppen, M. (2026). Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation. Journal of Biomedical Science, 33(1), Article 91. https://doi.org/10.1186/s12929-026-01290-7

Image Credits: AI Generated

DOI: 10.1186/s12929-026-01290-7

Keywords: ARDS, ADAM17, endothelial barrier, neutrophil migration, acute lung injury, vascular permeability, TNF-alpha, IL-6 signaling, JAM-A, VE-cadherin, LPS, pulmonary inflammation

The research team, led by Kaisi Yang and corresponding authors Yingshi Zhang and Qingchun Zhao, working across Shenyang Pharmaceutical University, the General Hospital of Northern Theater Command, and Wannan Medical University Affiliated Tongling People’s Hospital, assembled a multi-layered case for ADAM8/17’s involvement in this cancer. Their investigation began with bioinformatic mining of publicly available gene expression datasets, which revealed that ADAM8 is highly and specifically overexpressed in intrahepatic cholangiocarcinoma compared with surrounding tissue and other tumor types. This pattern of selective elevation is exactly what drug developers look for in a target: a molecule that is abundant in the disease but dispensable elsewhere, minimizing the risk of collateral toxicity.

Correlation alone, however, has long been a trap in cancer genomics. Many genes are merely passengers that ride along with tumor progression without causing it. To address this, the team turned to Mendelian randomization, a statistical technique that uses naturally occurring genetic variants as instruments to test whether an exposure, in this case ADAM8/17 expression, plausibly causes a disease outcome rather than simply accompanying it. By combining two-sample Mendelian randomization analyses with a meta-analysis across independent datasets, the researchers found that genetically influenced ADAM8/17 activity and its downstream Notch signaling pathway were closely linked to the occurrence and development of intrahepatic cholangiocarcinoma. This causal framing substantially strengthens the argument that these proteases are active participants in tumor biology rather than bystanders.

ADAM8 and ADAM17 are membrane-anchored enzymes known as sheddases, meaning they cleave the extracellular portions of other membrane proteins and release them into the surrounding environment. Among their substrates are signaling molecules and receptors that fuel inflammation, angiogenesis, and cell proliferation. The Notch pathway, which the study implicates as a downstream mediator, is a highly conserved cell-to-cell communication system that governs cell fate decisions; when dysregulated, it can promote tumor growth, epithelial-mesenchymal transition, and resistance to therapy. The idea that blocking ADAM8/17 could simultaneously dampen Notch-driven malignancy gives the target additional mechanistic appeal.

Identifying a target is only half the battle; the harder task is finding a molecule that disables it. Through molecular docking simulations, the team screened for small compounds capable of binding the catalytic machinery of ADAM8/17 and landed on a candidate they designated NY-2. To confirm that the compound genuinely engages its target inside cells rather than merely fitting a computational model, the researchers employed a cellular thermal shift assay. This technique exploits a simple physical principle: proteins stabilized by a bound ligand resist heat-induced denaturation. The assay demonstrated that NY-2 shifts the thermal stability of ADAM8/17 in cells, providing direct biochemical evidence of target engagement, a step that many candidate drugs fail to clear.

With target engagement established, the team moved into functional testing using an impressive battery of models. Patient-derived organoids, miniature three-dimensional tumor cultures grown from actual patient tissue, retain much of the cellular diversity and drug responsiveness of the original tumors, making them a far more faithful testing ground than conventional cell lines. In these organoids, alongside standard MTT proliferation assays, Transwell migration experiments, apoptosis measurements, and cell cycle analyses, NY-2 consistently suppressed the hallmarks of cancer progression: cells stopped dividing, migration was curtailed, and programmed cell death increased. The compound also arrested cells at specific checkpoints in the cell cycle, further choking off tumor expansion.

The mechanistic payoff came from western blotting experiments that mapped exactly which signaling cascades NY-2 disrupts. The results showed that the compound acts through two converging arms. The first is the Notch1–HIF1α–VEGFA axis, a chain in which Notch1 signaling stabilizes the hypoxia-inducible factor HIF1α, which in turn drives vascular endothelial growth factor A production, fueling the blood vessel growth that tumors need to enlarge and spread. The second is the Integrinα5–TGFβ–Smad pathway, in which the adhesion molecule integrin alpha-5 feeds into transforming growth factor beta signaling and its intracellular Smad effectors, a circuit intimately tied to epithelial-mesenchymal transition, the process by which cancer cells acquire invasive and metastatic properties. By suppressing both routes simultaneously, NY-2 attacks the tumor’s growth supply line and its invasion machinery at once.

The clinical significance of these findings is sharpened by the study’s prognostic data, which showed that high ADAM8/17 expression is associated with poor outcomes in patients with intrahepatic cholangiocarcinoma. This dual role, as both a biomarker of aggressive disease and a pharmacologically actionable target, is rare and valuable. It suggests a future in which ADAM8/17 expression levels could help stratify patients most likely to benefit from a targeted inhibitor, moving treatment away from one-size-fits-all chemotherapy toward precision oncology for a cancer that desperately needs it.

The authors are careful to frame this as a foundation rather than a finished therapy. Their stated next steps include gene editing experiments to confirm the target’s necessity and orthotopic liver tumor models, in which tumors are implanted directly into the liver to recreate the organ environment more faithfully than subcutaneous models. Such studies will be essential before any compound derived from NY-2 can approach clinical trials, and the history of cancer drug development is littered with promising preclinical targets that failed to translate. Nevertheless, the breadth of evidence here, spanning population genetics, structural biology, thermal proteomics, and patient-derived models, gives the ADAM8/17 hypothesis unusual depth.

For patients with intrahepatic cholangiocarcinoma, whose five-year survival remains dismal and whose treatment options have barely expanded in decades, the identification of a druggable, causally implicated target with a validated small-molecule inhibitor is a genuinely encouraging signal. The work also exemplifies a modern drug discovery paradigm: computational biology to nominate a target, Mendelian randomization to establish causality, docking and thermal shift assays to validate engagement, and organoids to demonstrate efficacy. If subsequent in vivo studies confirm what this research suggests, ADAM8/17 inhibition could become one of the most closely watched strategies in biliary tract cancer therapeutics.

Subject of Research: The role of ADAM8/17 proteases and the Notch1/Integrinα5 pathway in the development and targeted treatment of intrahepatic cholangiocarcinoma

Article Title: Novel drug target ADAM8/17 is associated with the occurrence of intrahepatic cholangiocarcinoma via Notch1/Integrinα5 pathway

Article References: Yang, K., Han, L., Song, X., Wang, C., Wang, Z., Zhu, Z., Xu, T., Mao, M., Xu, Z., Zhang, Y., & Zhao, Q. (2026). Novel drug target ADAM8/17 is associated with the occurrence of intrahepatic cholangiocarcinoma via Notch1/Integrinα5 pathway. Journal of Cancer Research and Clinical Oncology. https://doi.org/10.1007/s00432-026-06616-4

Image Credits: AI Generated

DOI: 10.1007/s00432-026-06616-4

Keywords: intrahepatic cholangiocarcinoma, ADAM8, ADAM17, NY-2 inhibitor, Notch1 signaling, Integrinα5, HIF1α, VEGFA, TGFβ-Smad pathway, Mendelian randomization, patient-derived organoids, targeted therapy