Matthew Jeffrey Uzelac

All Publications

• Obesity-related microbial dysbiosis as a potential modulator of tumour progression. Access microbiology Mokhashi, O., Chakladar, J., Li, W. T., Karin, M., Uzelac, M., Ongkeko, W. M. 2025; 7 (10)

  Abstract

  Although there is a well-established connection between the gut microbiome and obesity, the specific mechanisms by which microbes regulate cell signalling, inflammation and adipocyte growth to influence disease severity in obese patients remain largely unclear. Subsequently, while obesity itself is a well-established risk factor for various cancers, the exact mechanisms by which it drives disease progression are not yet definitively known. In this study, we explored the link between obesity-associated microbiome alterations and cancer progression by analysing microbial abundance in tissue samples from obese and cancer patients, and we identified specific microbes correlated with body mass index (BMI) that are associated with key cancer-related pathways. Notably, BMI-associated microbial species such as Pseudomonas fluorescens and Lactobacillus sakei were linked with both pro-tumour and anti-tumour progression in cancer patients. Additionally, microbes found to be abundant in cancer and obese tissue, such as Pseudomonas baetica, were significantly associated with the upregulation of certain oncogenic signalling pathways. BMI-associated microbes were also correlated with chemokine signalling and TFR2/NFkB-related genes. Both of these have well-established roles in inflammatory activity and inflammasome expression, a critical step in obesity-related cancer progression. Therefore, these microbes were found to be associated with variations in disease prognosis and patient survival. This study provides new insights into how obesity-related microbiome dysbiosis may be associated with cancer development and aims to introduce novel potential avenues for precision medicine approaches in cancer treatment.

  View details for DOI 10.1099/acmi.0.001055.v4

  View details for PubMedID 41132413

  View details for PubMedCentralID PMC12540031

• Computational Analysis Suggests That AsnGTT 3'-tRNA-Derived Fragments Are Potential Biomarkers in Papillary Thyroid Carcinoma. International journal of molecular sciences Do, A. N., Magesh, S., Uzelac, M., Chen, T., Li, W. T., Bouvet, M., Brumund, K. T., Wang-Rodriguez, J., Ongkeko, W. M. 2024; 25 (19)

  Abstract

  Transfer-RNA-derived fragments (tRFs) are a novel class of small non-coding RNAs that have been implicated in oncogenesis. tRFs may act as post-transcriptional regulators by recruiting AGO proteins and binding to highly complementary regions of mRNA at seed regions, resulting in the knockdown of the transcript. Therefore, tRFs may be critical to tumorigenesis and warrant investigation as potential biomarkers. Meanwhile, the incidence of papillary thyroid carcinoma (PTC) has increased in recent decades and current diagnostic technology stands to benefit from new detection methods. Although small non-coding RNAs have been studied for their role in oncogenesis, there is currently no standard for their use as PTC biomarkers, and tRFs are especially underexplored. Accordingly, we aim to identify dysregulated tRFs in PTC that may serve as biomarker candidates. We identified dysregulated tRFs and driver genes between PTC primary tumor samples (n = 511) and adjacent normal tissue samples (n = 59). Expression data were obtained from MINTbase v2.0 and The Cancer Genome Atlas. Dysregulated tRFs and genes were analyzed in tandem to find pairs with anticorrelated expression. Significantly anticorrelated tRF-gene pairs were then tested for potential binding affinity using RNA22-if a heteroduplex can form via complementary binding, this would support the hypothesized RNA silencing mechanism. Four tRFs were significantly dysregulated in PTC tissue (p < 0.05), with only AsnGTT 3'-tRF being upregulated. Binding affinity analysis revealed that tRF-30-RY73W0K5KKOV (AsnGTT 3'-tRF) exhibits sufficient complementarity to potentially bind to and regulate transcripts of SLC26A4, SLC5A8, DIO2, and TPO, which were all found to be downregulated in PTC tissue. In the present study, we identified dysregulated tRFs in PTC and found that AsnGTT 3'-tRF is a potential post-transcriptional regulator and biomarker.

  View details for DOI 10.3390/ijms251910631

  View details for PubMedID 39408960

• Assessing the diagnostic utility of tRNA-derived fragments as biomarkers of head and neck cancer. Translational oncology Uzelac, M., Ongkeko, W. M. 2024; 50: 102135

  Abstract

  Roughly 54,000 individuals are diagnosed with head and neck cancers in the United States yearly. Transfer RNA-derived fragments (tRF) are the products of enzymatic cleavage of precursor tRNAs, and have been proposed for use as biomarkers of head and neck cancer. In this study, we aim to further analyze the utility that tRFs might provide as biomarkers of head and neck cancer. tRF read counts were obtained for 453 tumor and 44 adjacent normal tissue samples and used to construct a gradient boosting diagnostic model. Although we identified 129 tRFs that were significantly dysregulated between these samples, the model achieved a sensitivity of only 69 % and a specificity of 59 %. tRFs are thought to induce the degradation of mRNA transcripts containing a complementary "seed" region. Despite the above performances, we chose to explore this concept of translational regulation by analyzing these tRFs for inverse correlation to the expression of select oncogenes and tumor suppressor genes implicated in head and neck cancer. Among others, CysGCA 5'-half and LysCTT 3'-tRF were upregulated in the tumor samples, and corresponded to decreased expression of PIK3R1, AKT1, and CPEB3. These transcripts were further found to contain numerous significantly complementary sites at which tRF-mediated mRNA degradation might occur. Although these tRFs did appear to correlate to many of the oncogenic metrics analyzed, we believe that additional research is needed before they might be used to improve the diagnosis, treatment, and survival of patients with this disease.

  View details for DOI 10.1016/j.tranon.2024.102135

  View details for PubMedID 39317063

• Microbiome Dysbiosis Is Associated with Castration Resistance and Cancer Stemness in Metastatic Prostate Cancer INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Uzelac, M., Xin, R., Ongkeko, W. M. 2024; 25 (6)

  Abstract

  Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration resistance often develops during the course of treatment, but its pathogenesis is poorly understood. This study explores the human microbiome for its implications in castration resistance and metastasis in prostate cancer. RNA sequencing data were downloaded for the bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These included both metastatic and adjacent normal biopsies. These sequences were mapped to bacterial sequences, yielding species-level counts. A vast majority of species were found to be significantly underabundant in the CRPC samples. Of these, numerous were found to correlate with the expression of known markers of castration resistance, including AR, PI3K, and AKT. Castration resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for a relation to these species. EGFR and SLC3A2 were widely downregulated, with a greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration resistance and stemness in prostate cancer. By considering the microbiome's importance in these factors, we may better understand the highly aggressive and highly invasive nature of castration-resistant prostate cancer, allowing for the needed improvements in the treatment of this disease.

  View details for DOI 10.3390/ijms25063291

  View details for Web of Science ID 001192914200001

  View details for PubMedID 38542265

  View details for PubMedCentralID PMC10970102

• Urinary Microbiome Dysbiosis and Immune Dysregulations as Potential Diagnostic Indicators of Bladder Cancer CANCERS Uzelac, M., Xin, R., Chen, T., John, D., Li, W., Rajasekaran, M., Ongkeko, W. M., Radziszewski, P., Zapala, L. 2024; 16 (2)

  Abstract

  There are a total of 82,290 new cases and 16,710 deaths estimated for bladder cancer in the United States in 2023. Currently, urine cytology tests are widely used for bladder cancer diagnosis, though they suffer from variable sensitivity, ranging from 45 to 97%. More recently, the microbiome has become increasingly recognized for its role in human diseases, including cancers. This study attempts to characterize urinary microbiome bladder cancer-specific dysbiosis to explore its diagnostic potential. RNA-sequencing data of urine samples from patients with bladder cancer (n = 18) and matched controls (n = 12) were mapped to bacterial sequences to yield species-level abundance approximations. Urine samples were analyzed at both the population and species level to reveal dysbiosis associated with bladder cancer. A panel of 35 differentially abundant species was discovered, which may be useful as urinary biomarkers for this disease. We further assessed whether these species were of similar significance in a validation dataset (n = 81), revealing that the genera Escherichia, Acinetobacter, and Enterobacter were consistently differentially abundant. We discovered distinct patterns of microbial-associated immune modulation in these samples. Several immune pathways were found to be significantly enriched with respect to the abundance of these species, including antigen processing and presentation, cytosolic DNA sensing, and leukocyte transendothelial migration. Differential cytokine activity was similarly observed, suggesting the urinary microbiome's correlation to immune modulation. The adherens junction and WNT signaling pathways, both implicated in the development and progression of bladder cancer, were also enriched with these species. Our findings indicate that the urinary microbiome may reflect both microbial and immune dysregulations of the tumor microenvironment in bladder cancer. Given the potential biomarker species identified, the urinary microbiome may provide a non-invasive, more sensitive, and more specific diagnostic tool, allowing for the earlier diagnosis of patients with bladder cancer.

  View details for DOI 10.3390/cancers16020394

  View details for Web of Science ID 001149040200001

  View details for PubMedID 38254883

  View details for PubMedCentralID PMC10814989

• tRNA-derived fragments (tRFs) as regulators of oncogenes and tumor suppressor genes in head and neck squamous cell carcinoma Uzelac, M., John, D., Chakladar, J., Li, W., Ongkeko, W. M. LIPPINCOTT WILLIAMS & WILKINS. 2023: E18082

  View details for DOI 10.1200/JCO.2023.41.16_suppl.e18082

  View details for Web of Science ID 001555441400035

• Racial and ethnic disparities associated with the intratumor microbiome in female cancers Uzelac, M., Li, W., Chakladar, J., John, D., Ongkeko, W. M. AMER ASSOC CANCER RESEARCH. 2023

  View details for DOI 10.1158/1538-7445.AM2023-LB110

  View details for Web of Science ID 001018089900328

• Effects of Human Papilloma Virus E6/E7 Oncoproteins on Genomic Structure in Head and Neck Squamous Cell Carcinoma CANCERS Uzelac, M., Barakchi, A., Beldona, V., John, D., Chakladar, J., Li, W., Ongkeko, W. M. M. 2022; 14 (24)

  Abstract

  Human Papilloma Virus (HPV) is highly prevalent within the U.S., with studies estimating that over 80% of individuals will contract the virus in their lifetime. HPV is considered a primary risk factor for the development and progression of oropharyngeal cancers. The impact of the HPV virus's E6 and E7 oncoproteins on cellular signaling pathways and genomic integration has been extensively characterized. Indirect genomic effects; however, remain relatively unidentified. In this study, we analyzed 83 HPV+ Head and Neck Squamous Cell Carcinoma (HNSCC) patients of varying HPV types. Expression counts of the HPV E6 and E7 oncogenes were estimated across samples and correlated with genomic mutational classes. High expression of E6 and E7 oncoproteins was associated with a greater number of total point mutations, especially on chromosomes 1, 11, and 17, which have been implicated in HPV-mediated cancers in previous studies. Samples with high E6 and E7 expression also exhibited more frequent non-clustered structural variation and a lack of clustered variation altogether. Copy number segments were present with fewer number of repeats in high E6 and E7 expression samples, which is known to correlate with decreased expression of affected genes. E6 and E7 expression was associated with increased activity of several cellular pathways associated in oncogenesis and telomere maintenance. In comprehensively characterizing the effects of the HPV oncoproteins on the human genome, potential mechanisms of HNSCC pathogenesis may be further elucidated.

  View details for DOI 10.3390/cancers14246190

  View details for Web of Science ID 000900549100001

  View details for PubMedID 36551675

  View details for PubMedCentralID PMC9777059

• The Intratumor Bacterial and Fungal Microbiome Is Characterized by HPV, Smoking, and Alcohol Consumption in Head and Neck Squamous Cell Carcinoma INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Chakladar, J., John, D., Magesh, S., Uzelac, M., Li, W., Dereschuk, K., Apostol, L., Brumund, K. T., Rodriguez, J., Ongkeko, W. M. 2022; 23 (21)

  Abstract

  Head and neck squamous cell carcinoma (HNSCC) tumor phenotypes and clinical outcomes are significantly influenced by etiological agents, such as HPV infection, smoking, and alcohol consumption. Accordingly, the intratumor microbiome has been increasingly implicated in cancer progression and metastasis. However, few studies characterize the intratumor microbial landscape of HNSCC with respect to these etiological agents. In this study, we aimed to investigate the bacterial and fungal landscape of HNSCC in association with HPV infection, smoking, and alcohol consumption. RNA-sequencing data were extracted from The Cancer Genome Atlas (TCGA) regarding 449 tissue samples and 44 normal samples. Pathoscope 2.0 was used to extract the microbial reads. Microbe abundance was compared to clinical variables, oncogenic signatures, and immune-associated pathways. Our results demonstrated that a similar number of dysregulated microbes was overabundant in smokers and nonsmokers, while heavy drinkers were characterized by an underabundance of dysregulated microbes. Conversely, the majority of dysregulated microbes were overabundant in HPV+ tumor samples when compared to HPV- tumor samples. Moreover, we observed that many dysregulated microbes were associated with oncogenic and metastatic pathways, suggesting their roles in influencing carcinogenesis. These microbes provide insights regarding potential mechanisms for tumor pathogenesis and progression with respect to the three etiological agents.

  View details for DOI 10.3390/ijms232113250

  View details for Web of Science ID 000881124000001

  View details for PubMedID 36362038

  View details for PubMedCentralID PMC9655846

• Archaea Microbiome Dysregulated Genes and Pathways as Molecular Targets for Lung Adenocarcinoma and Squamous Cell Carcinoma INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Uzelac, M., Li, Y., Chakladar, J., Li, W., Ongkeko, W. M. 2022; 23 (19)

  Abstract

  The human microbiome is a vast collection of microbial species that exist throughout the human body and regulate various bodily functions and phenomena. Of the microbial species that exist in the human microbiome, those within the archaea domain have not been characterized to the extent of those in more common domains, despite their potential for unique metabolic interaction with host cells. Research has correlated tumoral presence of bacterial microbial species to the development and progression of lung cancer; however, the impacts and influences of archaea in the microbiome remain heavily unexplored. Within the United States lung cancer remains highly fatal, responsible for over 100,000 deaths every year with a 5-year survival rate of roughly 22.9%. This project attempts to investigate specific archaeal species' correlation to lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) incidence, patient staging, death rates across individuals of varying ages, races, genders, and smoking-statuses, and potential molecular targets associated with archaea microbiome. Archaeal species abundance was assessed across lung tissue samples of 527 LUAD patients, 479 LUSC patients, and 99 healthy individuals. Nine archaeal species were found to be of significantly altered abundance in cancerous samples as compared to normal counterparts, 6 of which are common to both LUAD and LUSC subgroups. Several of these species are of the taxonomic class Thermoprotei or the phylum Euryarchaeota, both known to contain metabolic processes distinct from most bacterial species. Host-microbe metabolic interactions may be responsible for the observed correlation of these species' abundance with cancer incidence. Significant microbes were correlated to patient gene expression to reveal genes of altered abundance with respect to high and low archaeal presence. With these genes, cellular oncogenic signaling pathways were analyzed for enrichment across cancer and normal samples. In comparing gene expression between LUAD and adjacent normal samples, 2 gene sets were found to be significantly enriched in cancers. In LUSC comparison, 6 sets were significantly enriched in cancer, and 34 were enriched in normals. Microbial counts across healthy and cancerous patients were then used to develop a machine-learning based predictive algorithm, capable of distinguishing lung cancer patients from healthy normal with 99% accuracy.

  View details for DOI 10.3390/ijms231911566

  View details for Web of Science ID 000867749500001

  View details for PubMedID 36232866

  View details for PubMedCentralID PMC9570029

• Pan cancer analysis of the intra-tumoral microbiome's correlation with racial disparities. Li, W., Uzelac, M., Chakladar, J., Wong, L. M., Gnanasekar, A., Lee, A. C., John, D., Lopez, J., Ongkeko, W. M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.2519

  View details for Web of Science ID 000708120601041