Abstract
The tumor microenvironment compromises immune cells, extracellular matrix, as well as other cell types. These varying components alter the rate of passive diffusion of pharmacological agents, and it has especially been proven to be a barrier in the pancreatic cancer tumor microenvironment. Acinar to ductal metaplasia (ADM), is considered to be the initiating event of pancreatic ductal adenocarcinoma (PDAC), the process by which pancreatic acinar cells transdifferentiate into precancerous, ductal epithelial cells. Our lab has developed a 3D organoid assay to display ADM using primary, human pancreatic acinar cells to study the rate of transdifferentiation. Bulk-RNA sequencing analysis on our assay has shown a significant upregulation of cancer-signaling pathways as a result of ADM. Therefore, we hypothesized that the process of ADM is also an early event in promoting the stiffening microenvironment in PDAC. We have integrated the use of fluorescent nanoparticles into our assay to determine the biomechanical properties of the ADM microenvironment in relation to race. Using multiple particle tracking analysis, we have obtained information regarding the viscoelasticity and storage modulus of our 3D organoid assay. Preliminary data shows a stiffer microenvironment in Blacks/African Americans in comparison to other races (White=4, Hispanic=4, Black/African American=1), which can explain the poorer survival outcomes for Blacks/African Americans diagnosed with pancreatic cancer when undergoing chemotherapy. Collagen has also been shown to be a significant factor that affects the efficacy of anticancer agents. Data from bulk-RNA sequencing on our assay after 6 days of transdifferentiation additionally shows a significant upregulation of collagen production (COL1A1/2) as a result of ADM, with prior literature showing collagen subtype 1 to be the most abundantly found subtype in the tumor microenvironment. Future work consists of collecting additional donor samples to study the stiffness of the ADM microenvironment and collagen production in relation to race.
Citation Format: Corey Perkins, Jinmai Jiang, David Quashie Jr., Yating Mao, Jamel Ali, Thomas D. Schmittgen. Acinar to ductal metaplasia is the earliest event leading to the complexities of the pancreatic ductal adenocarcinoma tumor microenvironment in Blacks/African Americans [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 A075.
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