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.