Showing papers by "Thomas D. Schmittgen published in 2023"

Abstract C048: Computational pathway analysis of differentially expressed miRNAs in Black compared with White laryngeal squamous cell carcinoma

Abstract: Background: Black patients have maintained higher burden of laryngeal squamous cell carcinoma (LSCC), despite there being an overall decline in the rates of incidence and mortality across the U.S. population. A molecular basis for this disparity remains elusive. In recent years, studies have addressed head and neck disparities via protein coding genes, while ignoring the potential impact of non-coding RNA. Here we explore the manner in which differential expression of miRNAs in Black compared with White LSCC patients may influence the activation of various different downstream molecular pathways. Methods: Differential expression analysis was performed on a dataset generated from small RNA-sequencing of 32 LSCC tumors (16 derived from Black patients, 16 derived from White patients) using the R package DESeq2. For miRNAs identified as differentially expressed between Black and White patient tumors (-log2FC < -1 or log2FC > 1; p adjusted > 0.05) we generated a list of predicted mRNA targets using the R package miRNAtap. For miRNAs with significantly higher or lower expression in Black tumors compared with White tumors, we respectively combined their mRNA targets and performed KEGG pathway enrichment analysis on the lists of genes using the R package clusterProfiler. Results: From our dataset, we profiled 2051 miRNAs. Unsupervised clustering revealed a subset of 14 miRNAs that were significantly lower in expression in Black LSCCs compared to White LSCCs. KEGG pathway analysis showed that human immunodeficiency virus 1 pathway was significantly enriched for these miRNAs (p < 0.005). The GeneRatio for this pathway is greater than 0.60, indicating that around 60% of all genes in the human immunodeficiency virus 1 pathway are targeted by these lower expressed miRNAs. Significant gene targets identified are those involving the inflammatory signaling pathway including Raf-1, NFκB, and TNFR2. Conversely, we identified 7 miRNAs that were significantly higher in expression in Black LSCC compared to White LSCC. KEGG pathway analysis found the autophagy pathway to be significantly enriched for these miRNAs (p < 0.005). The GeneRatio for this pathway is greater than 0.40, indicating that over 40% of all genes in the autophagy pathway are targeted by these higher expressed miRNAs. Significant gene targets identified are those involved in cell survival signaling pathways including PI3K, AKT, JNK1, and PTEN. Conclusion: In summary, our computational findings highlight differential cell signaling pathways that may play a role in LSCC tumorigenesis in a race-dependent manner. Future directions for this work will involve additional pathway characterization through further computational analyses and biochemical studies. Citation Format: Chayil C. Lattimore, Heather Kates, Tongjun Gu, Jinmai Jiang, Thomas Schmittgen, Kristianna M. Fredenburg. Computational pathway analysis of differentially expressed miRNAs in Black compared with White laryngeal squamous cell carcinoma [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C048.

Abstract 5777: Race as a predictive confounder in the rate of transdifferentiation and drug response in human pancreatic acinar ductal metaplasia

Abstract: Pancreatic diseases (chronic pancreatitis, type 2 diabetes, pancreatic cancer) disproportionately affect the Black/African American (AA) community in comparison to non-White Hispanics and Whites. Acinar to ductal metaplasia (ADM), the process by which pancreatic acinar cells transdifferentiate into ductal epithelial cells, is believed to be an initiating event of pancreatic ductal adenocarcinoma. Our lab has developed a 3D organoid assay to display ADM using primary, human pancreatic acinar cells to study the rate of transdifferentiation amongst these three different races. Preliminary data shows that the rate of ADM is occurring significantly faster (p < 0.05) in Blacks/AAs (White=16, Hispanic=11, Black/AA=5), which may explain the disproportionately behind the incidence and mortality rates for this race in pancreatic cancer. A sigmoid Emax function best captured the longitudinal changes in the percentage of ADM in nonlinear mixed effects modeling analysis performed in Monolix. Covariate analysis on top of the selected model demonstrated that race was the only covariate affecting the individual trajectories in the percentage of ADM. We additionally use nanoparticles to study the biomechanical properties (I.e., viscoelasticity, storage modulus) of the ADM microenvironment which shows a stiffer microenvironment in Blacks/AAs than for the other races (White=4,Hispanic=4, Black/AA=1). Furthermore, we have used a histone deacetylase (HDAC) inhibitor in reversing the process of ADM, which has consequently shown race-related outcomes, with Blacks/AAs displaying a significant chemoresistance (p < 0.05) to HDAC treatment (White=6,Hispanic=6, Black/AA=3) by utilizing an ADM reversal index (ADMRI). Through further analysis, the plan is to continue procuring human samples from these three races to isolate an ADM-specific biomarker in relation race and drug reversal by studying the expression/activity of pancreatic associated genes by bulk-RNA and single-cell sequencing. Citation Format: Corey Melissa Perkins, Jinmai Jiang, Hesam Hakimjavadi, Jason Brant, Zhongyue Zhang, Ji-Hyun Lee, David Quashie, Yating Mao, Jamel Ali, Sarah Kim, Martha Campbell-Thompson, Thomas Schmittgen. Race as a predictive confounder in the rate of transdifferentiation and drug response in human pancreatic acinar ductal metaplasia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5777.