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Epigenetic regulation in muscle-invasive urothelial carcinoma of the bladder in the dog, a translational model of human cancer

Veterinary Oncology volume 1, Article number: 11 (2024) Cite this article

Abstract

Muscle-invasive urothelial carcinoma (MIUC) is the most common type of bladder malignancy in dogs, but the treatments used in the clinic are relatively ineffective for most of them. Dogs represent a naturally- occurring model for human MIUC and the advances in veterinary oncology could benefit human oncology as well. The field of epigenetics presents unique opportunities for new cancer therapeutics or biomarkers, as epigenetic modification of key genes can regulate tumor initiation and progression. This review summarizes the existing literature on epigenetic changes in canine MIUC as compared to human MIUC and provides suggestions for future studies that could benefit both human and canine patients.

Introduction

Muscle-invasive urothelial carcinoma of the bladder (MIUC, or invasive urothelial carcinoma, InvUC as has been previously described [1]) is the most common malignancy of the urinary bladder in dogs, and it is associated with high morbidity. This is partly because the disease is usually diagnosed at an advanced stage, as it is presented with non-specific clinical signs that are shared by other lower urinary tract disorders (LUTD), such as urinary tract infection or urolithiasis [2]. Advanced stages usually involve metastasis, leading to reduced quality of life, limited treatment options, and a poor prognosis involving pain, difficulty urinating, organ failure, and a shorter lifespan [3]. The current mechanisms of canine MIUC detection involve cytopathology, histopathology, and a recently developed urine test to identify BRAFV595E mutations, which are present in ~ 65–80% of canine MIUC [4, 5]. As such, there is a need for more efficient biomarkers for early disease diagnosis. Several studies have been undertaken to identify additional non-invasive biomarkers that could distinguish canine MIUC from other LUTD in the early stages [6]; however, none of them have as yet been implemented in the clinic. This includes microRNAs and various other markers identified by metabolomics, proteomics and lipidomics in the blood or urine. Several of these are now being considered for further clinical implementation. Treatment of canine MIUC involves the administration of NSAIDs, mainly piroxicam, either as a monotherapy (median survival 181 days [7]), or with the addition of chemotherapeutics (median survival 291 days [8]). Eventually clinical management of canine MIUC involves the sequential administration of different therapeutics leading to disease control in 75% of dogs and extending patient survival even further [9]. More effective therapeutics are urgently needed.

In 2023 there were approximately 82,000 new cases of human bladder cancer (BlCa) and 17,000 deaths from this disease in the United States [10]. The similarities and differences between human and canine MIUC are summarized by our group [11] and others [1, 12, 13]. In humans, MIUC is likely to metastasize, and the 5-year survival rate of patients with metastatic MIUC is 8% [14]. For patients with MIUC, cisplatin- or carboplatin -based combination chemotherapy regimens are the standard of care for first-line therapy for eligible patients, but more frequently now accompanied by immune checkpoint inhibitors against programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) [15]. Treatment with Enfortumab vedotin, an antibody drug conjugate, and the PD-1 inhibitor, pembrolizumab, was recently found superior to chemotherapy for patients with untreated locally advanced or metastatic MIUC [16]. Finally, erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor, was approved as the first targeted therapy for human patients with FGFR mutations that have progressed after chemotherapy [17].

Dogs are a model for human MIUC. Dogs and humans live in the same environment and, therefore, are exposed to the same predisposing risk factors. Canine and human MIUC tumors share pathophysiological characteristics, molecular mechanisms of initiation, progression and metastasis, response to therapeutics and mechanisms of drug resistance [11, 18]. Veterinary clinical trials could serve as an intermediate step between preclinical research and Phase 0 clinical trials in humans, enabling the selection of the most safe and efficient therapeutics and potentially improving the success rate of clinical trials overall [19]. Therefore, advances in veterinary oncology can benefit human oncology.

Epigenetic changes have been described in both canine and human cancers and shown to regulate tumorigenesis by “switching on and off” the expression of oncogenes, tumor suppressors or genes related to metastasis and drug resistance. In contrast to gene mutations that are permanent, epigenetic modifications may be reversed and are a field of active research both in human and canine malignancies [20]. In the past fifteen years, there have been several initiatives to map the human epigenome, focusing on epigenetics of disease and cancer such as the NIH Roadmap Epigenomics Consortium [21], the NIH Encyclopedia of DNA Elements (ENCODE) project [22], and the Epigenome Integration across Multiple Annotation Projects (EpiMap) Repository [23]. Recently, similar initiatives tried to generate a dog reference epigenome, such as BarkBase [24], and the groundbreaking Epigenome Catalog of the Dog (EpiC Dog) [25]. There are no cancer-specific canine epigenomic maps. Various epigenetic mechanisms have been reported in canine cancers, such as DNA methylation, histone modifications and transcriptional repression via non-coding RNAs. Apart from the therapeutic potential of targeting these modifications in the clinic, they could also be used as biomarkers for the early diagnosis of disease or monitoring of disease progression. This review summarizes the current landscape of epigenetic regulation of canine MIUC in comparison to other LUTD as well as human MIUC and provides recommendations for future directions that could benefit both dogs and humans.

MicroRNA -induced silencing of target genes

MicroRNAs (miRNA) represent a type of non-coding RNA that play crucial roles in cancer initiation and progression [26]. These small, ~ 17–22 nucleotides (nt) long non-coding RNAs regulate gene expression post-transcriptionally, “silencing” target genes by binding to homologous regions of mRNAs and resulting in translational obstruction and mRNA degradation (Fig. 1) [27]. Hundreds of studies have identified differentially expressed miRNA in human MIUC using tumor [28], blood [29, 30] or urine samples [31,32,33] alone or in pairs for analysis [34, 35]. Recently, a panel of 21 miRNAs was independently associated with a worse clinical outcome and reduced overall survival of human MIUC patients [36].

Fig. 1
figure 1

Epigenetic gene silencing in MIUC. Left: DNMTs catalyze the methylation of DNA CpG islands causing transcriptional repression. This process is reversed by 5-azac that activated transcriptions. Right: MiRNAs bind to complementary RNA molecules and lead to RNA degradation and translational repression. Abbreviations: DNMT: DNA methyltransferases, H3/4/2A/2B: Histones 3, 4, 2A or 2B, 5-azaC: 5-azacytidine

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MiRNA regulation is the most well-studied epigenetic modification in canine MIUC. The first study on canine miRNA was performed in 2012, and evaluated the expression levels of miR-103b, miR-34a, miR-16, miR106 and let-7c in tissues of dogs with MIUC (n = 18), inflammation of the bladder (n = 13) and healthy dogs (n = 4) [37]. In canine MIUC tumors, miR-34a and miR-106b were significantly upregulated compared to inflammatory bladder and healthy bladder tissue, and miR-103b and miR16 were higher in MIUC tumors versus inflammatory bladder disease (Table 1) [37]. Furthermore, let-7c was downregulated only in dogs with MIUC that received chemotherapy versus those that did not [37]. In 2017, we measured the same miRNAs in blood and urine of healthy dogs (n = 28), dogs with MIUC (n = 17), and dogs with other LUTD such as urinary tract infection or urinary stones (n = 25) [2]. When compared to healthy dogs, miR-103b was significantly downregulated in the blood of dogs with MIUC (p = 0.011) or LUTD (p = 0.028) whereas the other 4 miRNAs did not show any statistically significant differences [2]. In the urine, miR-103 and let7c were downregulated in MIUC and LUTD as compared to healthy dogs (p < 0.05) [2]. MiR-16 was significantly lower in dogs with MIUC versus those with LUTD (p = 0.0016) and miR-106b was downregulated in MIUC versus healthy dogs (p = 0.001) [2]. It should be emphasized that dogs with MIUC and other non-malignant LUTD present with similar clinical signs, so an effective biomarker needs to be able to differentiate between the two. While both of the abovementioned studies identified miR-16 as a potential diagnostic biomarker discriminating between the two conditions [2, 37], other authors used miR-16 as the reference gene for their quantitative Polymerase Chain Reactions (qPCRs) in a comparative study of miRNAs in different canine malignancies [38]. A reference gene serves as the internal control of the analysis and it is assumed that is stably expressed in all studied tissues and conditions [39] The selection of the reference gene is crucial for qPCR analyses since the levels of all identified miRNAs are then normalized against this gene to determine differential expression and significance as potential biomarkers. This discrepancy makes comparison between the findings of different studies difficult.

Table 1 MiRNA regulation in dogs with MIUC, LUTD or healthy dogs
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In 2017, Heishima et al. performed a comparative miRNA analysis in blood and tumors from dogs with epithelial malignancies (including MIUC), sarcomas, aggressive sarcomas, and healthy dogs [38]. Circulating miR-214 levels showed a moderate predictive potential for epithelial tumors (AUC = 0.75) compared to non-epithelial tumors (AUC = 0.83). Circulating miR-126 levels showed the highest diagnostic potential for epithelial tumors when compared to the control group (AUC = 0.95), and the combination of the two miRNAs showed sensitivity, specificity, and accuracy of 92.3%, 90.9% and 92% respectively for tumors of epithelial origin. However, the biomarkers were expressed by tumors of different origins, rendering them non-specific and unable to differentiate between different types of malignancies [38]. Finally, in 2022, RNA-Seq analysis of canine MIUC tumors (n = 5) and healthy bladder mucosa (n = 5) identified 28 miRNAs to be differentially expressed between MIUC vs LUTD [40]. 15 miRNAs were associated with well-established cancer pathways, such as p53, c-myc, ErbBB, Ras/ MAPK whereas 13 miRNAs were not associated with known canine MIUC pathways. Table 1 summarizes the findings from all the above cited studies.

MiRNA expression is tissue, context and, occasionally, species specific. Not all human miRNAs are conserved among other mammalian species [41]. In 2002, the online database “miRbase” was established. It is a central miRNA sequence database and registry, currently in version 22, responsible for nomenclature, sequence data and annotation of miRNAs from 271 organisms, including > 2,000 human and > 500 dog miRNA entries [42]. Other online databases provide information of predicted (targetscan [43], DIANA-microT [44], miRDB [45]) or experimentally validated (DIANA-TarBase-v8 [46], miRTarBase [47]) miRNA targets. In addition, there are recent human-specific and dog-specific miRNA atlases and databases. The first human miRNA atlas was constructed in 2016 and updated in 2021. MiRNATissueAtlas2 involves profiling of not only miRNAs, but of 9 classes of non-coding RNAs for 12 human tissues [48]. ExcellmiRDB is an online database compiling information about disease-specific human miRNAs identified in biofluids [49] miRmine is a database of human miRNA expression profiles, storing over 300 small RNA sequencing profiles of specific tissues, biofluids or cancer cell lines [50] In 2021, a pan-cancer atlas of somatic mutations in miRNA biogenesis genes was constructed, using samples from The Cancer genome Atlas (TCGA) repository [51]. Approximately 10,000 samples across 33 cancer types were analyzed and somatic mutations were identified in 29 genes related to miRNA biogenesis and function [52]. In 2023, the machine learning method Cancersig was used to identify cancer type- and cancer stage- specific miRNA for 15 cancer types. TCGA datasets of more 4,000 clinical samples were analyzed that contained miRNA sequence data and corresponding information on tumor staging. 242 miRNA were identified, including 35 miRNAs that could diagnose human UC with high sensitivity and specificity (AUC = 0.82) while distinguishing between early and late stages [53]. The first and only dog miRNA tissue atlas available was established in 2016 [54]. MiR-sequencing (miR-Seq) was performed in 16 tissues from healthy male beagle dogs to identify serum biomarkers that could diagnose test-article related organ-specific injury for toxicology studies. MiRNA sequence annotation identified tissue-specific expression that was highly conserved to human miRNA homologs [54]. To our knowledge, there are no disease-specific miRNA atlases for dogs.

Considering the fact that miRNAs are tissue and context specific in both humans [55, 56] and dogs [54, 57, 58], it is imperative to conduct next generation sequencing (miR-seq) analyses of MIUC tumors, blood and urine samples to identify all the miRNAs that are differentially expressed in dogs with MIUC of different breeds, sexes, in correlation with clinical staging and disease prognoses, other non-malignant LUTD, and healthy dogs and create a MIUC-specific atlas based on TNM classification. These studies could potentially identify novel miRNA biomarkers for canine MIUC early diagnosis or miRNA therapeutic targets whose function could be enhanced or inhibited with custom-made miRNA mimics or inhibitors, respectively.

DNA hypermethylation- another mechanism to “switch off” gene expression

DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs) and is characterized by the covalent transfer of a methyl group (CH3) to the fifth carbon of a cytosine residue (C5), forming 5-methylcytosine. This modification happens almost exclusively in 5’-cytosine-phosphate-guanine-3’ (CpG) islands (Fig. 1) [59, 60]. The promoters of tumor suppressor genes are usually hypermethylated and inactivated in cancer, resulting in gene “silencing”, which can cause tumor progression, drug resistance and/or hormone sensitivity [61]. Therefore, genome demethylation strategies, with DNMT inhibitors, have been an attractive approach in canine and human cancers [62]. Multiple preclinical studies and clinical trials have already examined drug-induced genome demethylation in human bladder cancer [63], whereas, urine [64] and blood [65] samples were assessed for DNA methylation patterns that could serve as biomarkers to diagnose human MIUC. In 2020, a DNA methylation map of human UC samples was used to potentially correlate methylation patterns with patient prognosis. 402 CpG islands were identified and grouped into 7 DNA methylation clusters, which could predict tumor TNM classification, stage, grade, patient age and survival [66]. This system could be potentially used by clinicians to create a personalized treatment plan based on disease severity that each patient is most likely to benefit from [66]. No such analysis has ever been performed in canine MIUC.

A few studies have recently investigated the canine DNA Methylome by using methylation array technologies for the study of selected methylation sites [67], Reduced representation bisulfite sequencing (RRBS) [68, 69] or RRBS combined with the Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) [70] to build canine DNA methylation “clocks” that could successfully predict chronological age. These technologies should be used to profile the DNA methylome and global chromatin accessibility of canine MIUC tumors as compared to healthy bladder tissue of different age and breed groupings, generating a plethora of information on MIUC pathobiology and potentially leading to novel therapeutic avenues.

To date, 5-azacytidine (or azacitidine) and decitabine are the only FDA-approved DNMT inhibitors available [71]. After establishing the anti-tumor preclinical efficacy of 5-azacytidine (5-azaC) in human MIUC (summarized in [63]), it was tested in a phase I clinical trial for 19 dogs with MIUC. 5-azaC was administered, in 28-cycles, and evaluated for safety, tolerability, urine pharmacokinetics and anti-tumor efficacy. 5-azaC was well tolerated and no treatment-related deaths were reported. The most prominent dose-dependent side effects were gastrointestinal (diarrhea, nausea, anorexia) or hematological (neutropenia, thrombocytopenia), which were reversible after treatment withdrawal5-azaC was detected in the urine within 6 h after single-dose administration. These toxicity and pharmacokinetic profiles were similar to the ones observed in humans treated with 5-azaC [72]. Finally, 5-azaC showed anti-tumor efficacy by reducing MIUC tumor size in 55.6%, leading to partial remission in 22%, and exhibiting overall disease control for 8 weeks in 72% of treated dogs, holding promise as a future therapeutic for canine, in addition to human, MIUC [62].

Histone acetylation- “switching on” gene expression

Histone modifications represent another mechanism of gene regulation. Histone modifications are covalent post-translational changes to histone tails, including H2A, H2B, H3 and H4 (Fig. 2) and include methylation, acetylation, phosphorylation, deimination, ADP-ribosylation, ubiquitylation, sumoylation [73], propionylation [74], and butyrylation [75]. Histone acetylation, mostly involved with transcriptional activation, is catalyzed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs). Dysregulation and enhanced activity of HDACs have been shown to drive tumor development by regulating cell cycle, apoptosis, DNA-damage response, autophagy, angiogenesis and metastasis [76]. Five HDAC inhibitors (HDACis) have been approved by the U.S. Food and Drug Administration (FDA) so far: vorinostat, romidepsin, belinostat, tucidinostat and Panobinostat [77]. HDACis showed great results in in-vitro studies with human MIUC cell lines but limited efficacy with increased toxicities in Phase II clinical trials for patients with MIUC. However, clinical efficacy was increased in Phase I/II when belinostat was combined with doxorubicin as compared to doxorubicin monotherapy in patients with soft tissue sarcoma [78]. Indeed, the use of combination therapies is among several modifications that have been proposed to minimize side effects while maximizing treatment efficacy [79] and should be further tested in human and canine MIUC.

Fig. 2
figure 2

“Switching on” gene expression in canine MIUC. Histone acetylation is catalyzed by HATs (normal urothelium) and reversed by HDACs (urothelial carcinoma). Vorinostat inhibits the action of HDACs, thereby activating gene expression. Abbreviations: HAT: Histone Acetyltransferase, HDAC: Histone deacetylase, H3/4/2A/2B: Histones 3, 4, 2A or 2B, 5-azaC: 5-azacytidine

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Vorinostat is the only HDACi that has been tested in canine MIUC cell lines. In 2019, Eto et al. screened 331 drugs for their anti-tumor potential against canine MIUC cell lines and identified 6 HDACi to be significantly enriched. Vorinostat, Trichostatin A and Scriptaid showed the highest anti-tumor efficacy with canine MIUC cell survival of 6.5%, 6.2% and 6.2% respectively. Vorinostat caused a dose-dependent reduction of cell viability in these 6 canine MIUC cell lines, as was reported in human MIUC cell lines [80]. Vorinostat caused G0/G1 cell cycle arrest through the upregulation of p21WAF1 and dephosphorylation of Rb and restored H3K9 (Histone H3 lysine 9) acetylation in a time-dependent manner. Vorinostat administration for 28 days caused a statistically significant reduction in positive tumor growth of canine MIUC cell line-derived xenografts. When assessing H3K9 levels in tumors from dogs with MIUC and healthy controls, they found that H3K9 was highly acetylated in normal urothelium, but the degree of acetylation varied in the MIUC tumor specimens. H3K9 deacetylation of canine MIUC tumors was correlated with shorter progression-free survival (p = 0.004), therefore poor prognosis [81]. Chronic repeated-dose toxicity and toxicokinetics of vorinostat were evaluated in Good Laboratory Practice (GLP) studies in Beagle dogs, after 26 weeks of oral administration [82]. Vorinostat was well tolerated, and the No Observed Adverse Effect Level (NOAEL) was set to 60 mg/kg/day. Oral half-life in dogs, which is the time required for 50% of the drug to be metabolized and eliminated from the body, was more than 5 h, equivalent to the oral human half-life which is approximately 1.34 h [82]. The proven anti-tumor efficacy of vorinostat in preclinical studies in-vitro and in-vivo studies with canine MIUC cell lines, in addition to acceptable safety and toxicokinetics profile in preclinical GLP studies, shows great potential for future Phase II clinical trials with vorinostat in dogs with MIUC.

Unexplored epigenetic mechanisms in canine MIUC

Apart from the epigenetic mechanisms mentioned above, there are other areas that have not been explored so far in canine MIUC, but data from other human and canine cancers show tremendous possibilities in this cancer type as well. These mechanisms involve the profiling of long non-coding RNAs and histone modifications and the use of CRISPR/Cas9 to manipulate the epigenome.

Long non-coding RNAs

Long non-coding RNAs (lncRNAs) are another type of non-coding RNAs, longer than 200 nucleotides in length. LncRNAs are not translated into proteins but contribute to gene regulation by post-transcriptional and translational regulation. In the context of cancer, LncRNAs are involved in cellular responses after DNA damage, epithelial-to-mesenchymal transition, escape of immune recognition, stemness and represent emerging therapeutic targets [83]. Abnormal expression of lncRNAs has been associated with human MIUC progression and drug resistance [84]. LncRNAs can also bind to complementary miRNAs, blocking the repression of their target molecules. This mechanism of competing with endogenous RNA molecules for the same miRNA molecules could be exploited for the development of new therapeutics for human MIUC [85].

The molecular function and clinical utility or lncRNAs for canine mammary tumors, melanomas, lymphomas, osteosarcomas, soft tissue and histiocytic sarcomas in comparison to the corresponding human malignancies, were recently summarized elsewhere [86]. No work has been performed in canine MIUC cell lines or tumors. A recent study that identified 10,444 canine lncRNAs in 26 distinct tissue types, showed that the expression of 44% of canine lncRNAs is tissue specific [87], highlighting the importance of studying this epigenetic mechanism separately in each tumor type, including canine MIUC.

Other histone modifications

Apart from histone acetylation, there are other histone modifications, as mentioned above. Histone methylation involves the addition of methyl groups to lysine or arginine residues of histones and can lead to either transcriptional activation or repression [88]. Histone methylation is catalyzed by histone methyltransferases (HMTs) and reversed by histone demethylases (HDMs) [89]. The levels of the HMT enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) were higher in human MIUC tumors as compared to normal tissues (p < 0.05) and associated with higher tumor stage (P = 0.026) and grade (P < 0.001) [90]. Urinary levels of EZH2 showed high diagnostic ability for MIUC (p < 0.001) but not for non-MIUC (p > 0.05) and could differentiate between MIUC and non-MIUC (AUC = 0.787) [91]. The role of EZH2 and other HMT have never been studied in canine MIUC tumorigenesis, tumor progression and their potential as diagnostic biomarker or therapeutic targets should be further explored. Considering the technology that is now available to profile histone modifications such as histone acetylation, deacetylation and methylation quantification, methyltransferase and demethylase assays, phosphorylation, ubiquitination and SUMOylation profiling [92], there is tremendous potential for the characterization of both canine and human MIUC tumors and the development of targeted therapies.

Crispr/Cas9

Clustered regularly interspaced palindromic repeats (CRISPR/Cas9) technology has revolutionized gene-editing. Cas9 protein is coupled with a 20-nt guide sequence complementary to target DNA. Cas9 cleaves the targeted DNA sequence enabling it to accurately edit DNA where it was cut. It can be applied to various diseases, including genetic disorders, viral diseases or cancer [93]. The first CRISPR/Cas9-based treatment was recently approved by the FDA for sickle cell-disease [94] opening tremendous potential for other diseases, as well. Apart from modulating DNA sequences, CRISPR/Cas9 knock-in and CRISPR/dCas9-Tet1 systems can target and reverse the silencing of specific genes by demethylation of their promoter’s CpG sites. This provides an advantage to “traditional” drug-induced DNA promoter demethylation that is non-specific in nature [95]. Newer technologies like CRISPRoff [96] or an enzyme-free CRISPR/dCas9-based system [97] were discovered to complement traditional CRISPR/Cas9 by reducing the non-specific targeting in the cell, opening up possibilities for safer CRISPR-based therapy of epigenetic modifications in human and veterinary oncology, including canine patients with MIUC.

Tools for the study of canine MIUC pathobiology

Even though human MIUC cell lines have been available for more than 35 years [98] and thoroughly characterized [99], the establishment of the first canine MIUC cell line did not happen until 1995, followed by another seven lines in 2008 from Purdue University [100, 101]. Afterwards, more cell lines were established and made available by multiple research groups [100, 102,103,104,105]. In 2016, the Flint Animal Cancer Center in Colorado performed transcriptomic, miRNomic and histopathological characterization along with drug screening of a panel of 28 canine cancer cell lines, including MIUC cell lines [106]. The thorough epigenomic characterization of these cell lines will lead to groundbreaking discoveries, enable more efficient screening of therapeutics, and personalized treatments as well as the most efficient translation of findings from the “bench to the bedside” of veterinary and human patients.

Data availability

No datasets were generated or analysed during the current study.

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The contents reported/presented within do not represent the views of the Department of Defense or the United States Government.

Funding

M.M.T. was funded by the Maxine Adler and Lodric Maddox Fellowship Awards, UC Davis School of Veterinary Medicine.

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Authors and Affiliations

  1. Veterans Affairs-Northern California Health Care System, Mather, CA, 95655, USA

    Maria Malvina Tsamouri, Maria Mudryj & Paramita M. Ghosh

  2. Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95718, USA

    Maria Malvina Tsamouri & Paramita M. Ghosh

  3. Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA

    Michael S. Kent

  4. Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, 95616, USA

    Maria Mudryj

  5. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA, 95616, USA

    Paramita M. Ghosh

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Conceptualization, M.M.T.; Original draft preparation, M.M.T.; Review and editing, M.S.K., M.M., P.M.G.; Supervision, P.M.G.

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Tsamouri, M.M., Kent, M.S., Mudryj, M. et al. Epigenetic regulation in muscle-invasive urothelial carcinoma of the bladder in the dog, a translational model of human cancer. Vet. Oncol. 1, 11 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s44356-024-00011-2

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Veterinary Oncology

ISSN: 3004-9814

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