Seelig, Davis

Diffuse B-cell lymphomas are the most prevalent canine hematologic malignancies, and their clinical presentation resembles that of human B-cell non-Hodgkin lymphomas (NHLs). However, a lack of a clear subtyping framework perpetuates imprecise treatment approaches that fail to address mechanisms of therapy resistance. Here, we employed deep phenotyping via serial sampling and longitudinal transcriptomics to evaluate intratumoral composition and therapy response in a 6-year-old neutered male goldendoodle with stage 5A marginal zone lymphoma (MZL). Following sequential treatment consisting of a single IV dose of oncolytic vesicular stomatitis virotherapy (VSV) and standard CHOP chemotherapy 30 days later, we performed scRNAseq on seven serial lymph node biopsies and spatial sequencing on a resection taken 10 days post-VSV treatment. B cells (>90%) comprised three transcriptionally distinct and temporally stable subpopulations, with specific copy number profiles and robust spatial organization despite disrupted lymph node architecture. Analysis across subpopulations revealed downregulation of the quiescence program including KLF2, suggesting similarity to KLF2-deficient human MZL. While VSV successfully reached target B cells, downstream transcriptional responses were predominantly localized to the T-cell compartment. T cells (≤6%) showed increased proliferation and upregulation of cytotoxicity markers post-VSV administration, enriching for leukocyte-mediated cytotoxicity pathways consistent with an anti-viral immune response. Ultimately, these results provide an in vivo proof-of-concept for the treatment paradigm in canine lymphoma, while emphasizing the need for improved subtyping frameworks and multidimensional treatment strategies targeting intratumoral heterogeneity.

Abstract Introduction: Lymphomas are among the most common malignancies in dogs, and their morphologic and biological similarities to human counterparts have established them as widely accepted models of human disease. However, emerging molecular data suggest that conservation varies by subtype, and that many common lymphoma subtypes are principally convergent rather than homologous conditions, requiring a critical reassessment of when and how canine lymphomas provide relevant models of human disease. Methods: We employed conventional pathology, immunohistochemistry, and next generation sequencing platforms, including single-cell sequencing and spatial genomics, to characterize the transcriptional landscape and cellular organization of canine lymphomas, complemented by population metadata. Results: Our analysis revealed that canine DLBCL lacks the traditional GCB/ABC bifurcation seen in humans. While activation of NFκB pathways is seen commonly in these tumors, a germinal center-like DLBCL subtype is not apparent in dogs, and the transcriptional signatures are distinct from those of activated B-cell like DLBCL. Instead, we identified a novel canine-specific DLBCL subset driven by an AP-1-associated transcriptional signature, mirroring advanced human follicular lymphoma rather than human DLBCL. In contrast, emerging data suggest that downregulation of quiescence programs might be a shared feature of both human and canine MZLs, making this subtype a candidate for conserved disease mechanisms. While canine T-cell lymphomas exhibited extensive transcriptional heterogeneity, the samples in our dataset did not align with established human T-cell subgroups, suggesting that high incidence in dogs might not equate to molecular similarity. Conclusions: Our results suggest canine and human lymphomas are principally convergent rather than homologous diseases whose evolution and topological organization are constrained by developmental programs. The distinct transcriptional programs of canine and human DLBCLs reveal informative biological divergence, while potential shared features of MZL suggest contexts where comparative oncology may illuminate conserved disease mechanisms. Canine T-cell lymphomas exhibit extensive transcriptional heterogeneity that, at present, defies simple classification, mirroring challenges in their human counterparts and underscoring the need for larger studies to establish molecular patterns that inform causation, prognosis, and treatment. These findings highlight contexts where distinct and conserved molecular features between canine and human lymphoma can reveal shared and divergent disease mechanisms, ultimately underscoring the need for subtype-specific validation as canine lymphomas are adopted as models of human disease. Use of AI: Generative AI was used to improve clarity and readability of the abstract. AI was not used to conduct the study or to produce new text or material. Citation Format: Jaime F. Modiano, Amy E . Treeful, Grace E. Walker, Davis M. Seelig, Caitlyn M. Callaghan, Timothy D. O'Brien, Shruthi Naik, Aaron L. Sarver. Different paths to the same destination: Molecular divergence and functional convergence in human and canine lymphomas [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A023.

Background: Airway stenting is a critical intervention to restore airway patency, yet complications such as stent migration, mucostasis, airway injury, and granulation tissue formation remain major concerns. Although various covering materials have been explored, the effectiveness of amniotic membrane (AM) as a stent cover has not been evaluated. This study is the first to assess airway-related complications of a novel AM-covered self-expandable metallic stent (SEMS) compared with a commercially available synthetic polymer-covered SEMS. To compare the incidence of stent-related complications between AM-covered SEMS and synthetic polymer-covered SEMS over a 90-day in vivo survival period. Methods: Eight adult Yucatan miniswine were implanted with either an AM-covered or control stent and monitored over 90 days with bronchoscopic evaluations at 4 timepoints. Histologic assessments were performed at termination. Results: Seven animals completed the study (4 AM stents, 3 controls). One control animal was terminated early due to stent expectoration. AM-covered stents were associated with reduced stent migration, mucostasis, and granulation tissue formation compared with controls. Histologic analysis revealed significantly less airway injury and evidence of re-epithelialization with cilia in the AM group; a feature absent in control stents. One animal was excluded at implantation and replaced due to a procedural complication unrelated to the stent. Conclusion: This is the first study to evaluate stent-related complications of AM-covered airway stents. The results demonstrate that AM-covered SEMS reduce airway injury and common complications associated with synthetic polymer-covered stents. These findings suggest that AM-coverings may enhance biocompatibility and integration while mitigating adverse airway responses. Larger studies and human clinical trials are needed to validate these results and explore clinical application.

A three year old male neutered mixed breed dog presented with a mass on the right carpus and accompanying lameness. A Jamshidi bone biopsy was performed, and histopathology results were consistent with a sarcoma. The dog received oncolytic virotherapy (OV) with vesicular stomatitis virus (VSV) as part of a clinical trial in dogs with osteosarcoma (OSA). Ten days after VSV treatment, the affected limb was amputated, and histopathology was consistent with intramedullary HSA. Considering the new diagnosis, standard doxorubicin chemotherapy was prescribed. With this combination of therapies, the dog had an extended survival of more than seven years and remains alive at the time of writing. This is the first case report documenting OV given in conjunction with the standard of care for canine appendicular HSA.

It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study’s findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.