Biology subjects

Seelig, D. M.

Publications and source records attributed to Seelig, D. M..

4 recordsLinked to original sources

bioRxiv2026

Longitudinal single-cell and spatial transcriptomics reveals intratumor heterogeneity, therapeutic response, and comparative value of canine marginal zone lymphoma

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.

cancer biology↗

bioRxiv2023

Deletion of Glyoxalase 1 exacerbates acetaminophen-induced hepatotoxicity in mice

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC) has a narrow therapeutic window and early treatment is essential for satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late-presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end-products (AGEs) and consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase-1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in APAP mediated activation of RAGE and downstream cell-death cascades. Constitutive Glo-1 knockout mice (GKO) and a cofactor of Glo-1, {psi}-GSH, were employed as tools. Our findings show elevated oxidative stress, activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild type controls. A unique feature of the hepatic necrosis in GKO mice is the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than inflammation seen in wild type. The GSH surrogate and general antioxidant, {psi}-GSH alleviated APAP toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against initial stages of APAP overdose.

pharmacology and toxicology↗

bioRxiv2023

Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars

Diffuse midline glioma (DMG) is a leading cause of brain tumor death in children. In addition to hallmark H3.3K27M mutations, significant subsets also harbor alterations of other genes, such as TP53 and PDGFRA. Despite the prevalence of H3.3K27M, the results of clinical trials in DMG have been mixed, possibly due to the lack of models recapitulating its genetic heterogeneity. To address this gap, we developed human iPSC-derived tumor models harboring TP53R248Q with or without heterozygous H3.3K27M and/or PDGFRAD842V overexpression. The combination of H3.3K27M and PDGFRAD842V resulted in more proliferative tumors when gene-edited neural progenitor (NP) cells were implanted into mouse brains compared to NP with either mutation alone. Transcriptomic comparison of tumors and their NP cells of origin identified conserved JAK/STAT pathway activation across genotypes as characteristic of malignant transformation. Conversely, integrated genome-wide epigenomic and transcriptomic analyses, as well as rational pharmacologic inhibition, revealed targetable vulnerabilities unique to the TP53R248Q; H3.3K27M; PDGFRAD842V tumors and related to their aggressive growth phenotype. These include AREG-mediated cell cycle control, altered metabolism, and vulnerability to combination ONC201/trametinib treatment. Taken together, these data suggest that cooperation between H3.3K27M and PDGFRA influences tumor biology, underscoring the need for better molecular stratification in DMG clinical trials.

genomics↗

bioRxiv2021

Comparison of Chronic Wasting Disease Detection Methods and Procedures: implications for free-ranging white-tailed deer (Odocoileus virginianus) surveillance and management

Throughout North America, chronic wasting disease (CWD) has emerged as perhaps the greatest threat to wild cervid populations, including white-tailed deer (Odocoileus virginianus). White-tailed deer are the most sought after big game species across North America with populations of various subspecies in nearly all Canadian provinces, the contiguous USA, and Mexico. Documented CWD cases have dramatically increased across the white-tailed deer range since the mid-1990s, including in Minnesota. CWD surveillance in free-ranging white-tailed deer and other cervid populations mainly depends upon immunodetection methods (e.g., immunohistochemistry [IHC] and enzyme-linked immunosorbent assay [ELISA]) on medial retropharyngeal lymph nodes and obex. More recent technologies centered on prion protein amplification methods of detection have shown promise as more sensitive and rapid CWD diagnostic tools. Here, we used blinded samples to test the efficacy of real time quaking-induced conversion (RT-QuIC) in comparison to ELISA and IHC for screening tissues, blood, and feces collected in 2019 from white-tailed deer in southeastern Minnesota, where CWD has been routinely detected since 2016. Our results support previous findings that RT-QuIC is a more sensitive tool for CWD detection than current antibody-based methods. Additionally, a CWD testing protocol that includes multiple lymphoid tissues (medial retropharyngeal lymph node, parotid lymph node, and palatine tonsil) per animal may effectively identify a greater number of CWD detections in a white-tailed deer population than a single sample type (i.e., medial retropharyngeal lymph nodes). These results reveal that the variability of CWD pathogenesis, sampling protocol, and testing platform must be considered for the effective detection and management of CWD throughout North America.

ecology↗