Publications

Abstract Background Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. Methods We developed a novel morphology-based screen using organoids from wildtype and p48 Cre/+ (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA). Results Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis. The class I HDAC inhibitors apicidin and FK228, and the histone methyltransferase inhibitor chaetocin demonstrated pronounced ADM inhibition and reversal without inducing significant cytotoxicity at 1 µM. Thioester prodrug class I HDAC inhibitor largazole attenuated ADM while its disulfide homodimer was effective in both ADM inhibition and reversal. Prioritized compounds were validated for ADM reversal in p48 Cre/+ ;LSL-Kras G12D/+ (KC) mouse organoids using both morphological and molecular endpoints. Molecular index analysis of ADM reversal in KC mouse organoids demonstrated improved activity compared to TSA. Improved prodrug stability translated into a stronger phenotypic and molecular response. RNA-sequencing indicated that angiotensinogen was the top inhibited pathway during ADM reversal. Conclusion Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.

In Fig. 5A, the Western blot bands showing FOXP1 and GAPDH expression in SK-Hep1 cells were also used to show FOXP1 and GAPDH expression in SNU-449 cells.

Supplementary Tables S1-S5 from Association of MicroRNA Expression in Hepatocellular Carcinomas with Hepatitis Infection, Cirrhosis, and Patient Survival

This study is the first to identify and define miRNA expression in circulating plasma microvesicles of normal subjects. The data generated from this study provides a basis for future studies to determine the predictive role of peripheral blood miRNA signatures in human disease and will enable the definition of the biological processes regulated by these miRNA.

Abstract Pancreatic ductal adenocarcinoma is believed to arise from exocrine acinar cells following trans-differentiation to cells with a more epithelial phenotype. A pancreas enriched cluster of miRNAs (miR-216a/b-217) is located on chromosomes 2 and 11 in humans and mice, respectively. These miRNAs are significantly reduced in patient's tumor specimens and during tumor progression in a transgenic mouse model of pancreatic ductal adenocarcinoma. To investigate a role for miR-216/-217 during acinar ductal trans-differentiation, we used a model by which primary mouse pancreatic acini trans-differentiate into epithelial-like cells when cultured on matrigel. Over a 4 day culture period, the acini develop an epithelial morphology and display reduced mRNA expression of the acinar marker amylase, increased expression of the epithelial marker cytokeratin-19 (KRT19) and reduced expression miR-216/-217. Forced expression of miR-217 using a lentiviral vector (LV) decreased KRT19 mRNA expression compared to the empty vector control treated cells on day 4 of the trans-differentiation. To implicate miR-217 targets in regulating acinar trans-differentiation, we considered REST/NRSF, a transcriptional repressor of neuronal genes in non-neuronal tissues. REST mRNA expression increased during the 4 day trans-differentiation implying regulation of REST by miR-217. Regulation of REST by miR-217 was validated using a luciferase assay and western blotting. Furthermore, two REST target genes were upregulated by the miR-217 LV on day 4 of the trans-differentiation. Studies are ongoing to determine if this increase in expression results from miR-217 suppressing REST protein levels. Additionally, miR-217 LV infection of 3 pancreas cancer cell lines reduced REST protein and caused significant cell death. Our current focus is to establish a link between miR-217 suppression of REST and cell death. We report a connection between reduced miR-217 in several pancreas model systems. We hypothesize a novel role for REST in pancreas homeostasis and cancer. Citation Format: Ana Clara P. Azevedo-Pouly, Jinmai Jiang, Dhruvitkumar Sutaria, Thomas Schmittgen. Regulation of NRSF/REST by miR-217; Implications during pancreatic acinar ductal trans-differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4187. doi:10.1158/1538-7445.AM2013-4187

We summarize the risk factors that may significantly contribute to racial disparities in pancreatic cancer, which is now the third leading cause of cancer deaths and projected to be second around 2030 in 12 years. For decades, the incidence rate of pancreatic cancer among Blacks has been 30% to 70% higher than other racial groups in the United States and the 5-year survival rate is approximately 5%. Diabetes and obesity have been identified as potentially predisposing factors to pancreatic cancer and both are more common among Blacks. Smoking continues to be one of the most important risk factors for pancreatic cancer and smoking rates are higher among Blacks compared to other racial groups. The overall risk of pancreatic cancer due to changes in DNA is thought to be the same for most racial groups; however, DNA methylation levels have been observed to be significantly different between Blacks and Whites. This finding may underlie the racial disparities in pancreatic cancer. Identification and prevention of these factors may be effective strategies to reduce the high incidence and mortality rates for pancreatic cancer among Blacks.

Supplementary Data from MicroRNAs modulate the chemosensitivity of tumor cells

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Abstract Cancer-associated adipocytes (CAAs) are key components of the pancreatic tumor microenvironment, yet how their phenotype and function are regulated by environmental conditions remains poorly understood. Here, we demonstrate that oxygen tension and matrix stiffness dramatically alter CAA behavior and their subsequent effects on pancreatic ductal adenocarcinoma (PDAC) progression. Under normoxic conditions and soft matrix, CAAs exhibit an activated phenotype characterized by extended podia formation and enhanced secretion of matrix-degrading enzymes, particularly MMP-2 and MMP-9, leading to dissolution of organoid extracellular matrix (ECM) and restriction of PDAC cell growth through direct cell-cell contact. In contrast, when cultured within stiff ECM environments (∼30 kPa), CAAs maintain a rounded, stem cell-like morphology without matrix-degrading activity, but notably promote PDAC cell migration. Gene expression confirmed that ECM-primed CAAs revealed upregulation of stemness markers including OCT4, SOX2, and SOX9, along with enhanced expression of pro-inflammatory cytokines. Using ectopic pancreatic tumor models, we found that CAAs primed in stiff ECM significantly accelerate tumor progression and invasion compared to controls, with increased tumor volume and invasion into the muscle layer 4 weeks post-implantation. Mechanistically, stiff ECM-primed CAAs showed distinct stem cell-like phenotype and altered secretome profiles. When cocultured with PDAC cells, their crosstalk promoted increased secretion of pro-inflammatory cytokines IL-6 and TNF-α while downregulating anti-inflammatory cytokine IL-10, creating a more tumor-supportive microenvironment. IHC reveals macrophage F4/80 showed no significant difference between groups, however, CD163+ macrophages were more prevalent at the early stage in the inactivated CAA-PDAC group. These findings reveal previously unrecognized plasticity in CAA function regulated by mechanical and oxygen tension cues, suggesting that the spatial distribution of these environmental factors within pancreatic tumors may create distinct zones of tumor promotion versus restriction. Our results highlight the complex role of CAAs in PDAC progression and suggest that targeting ECM stiffness could be a strategy to modify CAA behavior for therapeutic benefit. Understanding this mechanical control of CAA function could lead to novel therapeutic strategies for PDAC treatment. Citation Format: Bo Han, Zhi Yang, Shuqing Zhao, Thomas Schmittgen, Jamel Ali, Jonathan Barajas, Carolyn Ruiz-Rivera, Ba Xuan Hoang. Mechanical control of cancer-associated adipocyte plasticity orchestrates pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1234.

Supplementary Data from MicroRNAs modulate the chemosensitivity of tumor cells