Pancreatic acinar cells display a remarkable degree of plasticity and can dedifferentiate into ductal-like progenitor cells by a process known as acinar ductal metaplasia (ADM). ADM is believed to be one of the earliest precursor lesions toward the development of pancreatic ductal adenocarcinoma and maintaining the pancreatic acinar cell phenotype suppresses tumor formation. The effects of a novel pStat3 inhibitor (LLL12B) and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) were investigated using 3-D cultures from p48Cre/+ and p48Cre/+LSL-KrasG12D/+ (KC) mice. LLL12B and TSA inhibited ADM in both KC and p48Cre/+ mouse pancreatic organoids. Furthermore, treatment with LLL12B or TSA on dedifferentiated acini from p48Cre/+ and KC mice that had undergone ADM produced morphologic and gene expression changes that suggest a reversal of ADM. Validation experiments using qRT-PCR (p48Cre/+ and KC) and RNA sequencing (KC) of the LLL12B and TSA treated cultures showed that the ADM reversal was more robust for the TSA treatments. Pathway analysis showed that TSA inhibited Spink1 and PI3K/AKT signaling during ADM reversal. The ability of TSA to reverse ADM was also observed in primary human acinar cultures. We report that pStat3 and HDAC inhibition can attenuate ADM in vitro and reverse ADM in the context of wild-type Kras. Our findings suggest that pharmacological inhibition or reversal of pancreatic ADM represents a potential therapeutic strategy for blocking aberrant ductal reprogramming of acinar cells.

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Diseases of the pancreas (i.e. chronic pancreatitis, diabetes and pancreatic cancer) disproportionally affect the African American community. Challenges associated with engaging the African American community in biospecimen research are longstanding. We surveyed a number of pancreas-related biobanks and data repositories for African American representation. While some of the biobanks and databases surveyed contain biospecimens and data from African American donors at levels that reflect minority representation among the general population, others do not. A number of factors have historically contributed to reduced participation of the African Americans community in biospecimen donation including medical mistrust, lack of transparency, fear and a poor knowledge and understanding about the use of biospecimens for research. Suggestions for increasing African American participation in organ and biospecimen donation include educational interventions, particularly in community groups, and providing printed and online recruitment materials to patients, patient advocates and care partners. Increasing awareness of the many benefits of biospecimen donation among African Americans will positively affect health disparities research into pancreatic cancer and other diseases. Citation Format: Linda Behar-Horenstein, Rueben C. Warren, V. Wendy Setiawan, Corey M. Perkins, Thomas D. Schmittgen. Enhancing African American participation in biospecimens: A case in point for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-236.

Pancreatic diseases (acute/chronic pancreatitis, type 2 diabetes, pancreatic cancer) disproportionately affect the Black/African American 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 among these three different races. Preliminary data shows that the rate of ADM is occurring significantly faster (p < 0.05) in Blacks/African Americans (White=11, Hispanic=10, Black/African American=5), which may explain the disproportionately behind the incidence and mortality rates for this race in pancreatic diseases. 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/African Americans than for the other races (White=4, Hispanic=4, Black/African American=1). Furthermore, I study the use of histone deacetylase (HDAC) inhibitors in reversing the process of ADM, which has consequently shown race-related outcomes, with Blacks/African Americans 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 Perkins, Jinmai Jiang, Hesam Hakimjavadi, David Quashie Jr, Yating Mao, Jamel Ali, Thomas D. Schmittgen. Race plays a role on the rate of transdifferentiation in human pancreatic acinar ductal metaplasia and its' drug response [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR003.

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.