Pharmacological inhibition and reversal of pancreatic acinar ductal metaplasia

Lais da Silva; Jinmai Jiang; Corey Perkins; Kalina Rosenova Atanasova; Julie K Bray; Gamze Bulut; Ana Azevedo-Pouly; Martha Campbell-Thompson; Xiaozhi Yang; Hesamedin Hakimjavadi; Srikar Chamala; Ranjala Ratnayake; Raad Z Gharaibeh; Chenglong Li; Hendrik Luesch; Thomas D Schmittgen

doi:10.1038/s41420-022-01165-4

Pharmacological inhibition and reversal of pancreatic acinar ductal metaplasia

Cell Death Discov. 2022 Sep 2;8(1):378. doi: 10.1038/s41420-022-01165-4.

Authors

Lais da Silva^#¹, Jinmai Jiang^#¹, Corey Perkins^#¹, Kalina Rosenova Atanasova^{2

3}, Julie K Bray⁴, Gamze Bulut¹, Ana Azevedo-Pouly⁵, Martha Campbell-Thompson⁴, Xiaozhi Yang², Hesamedin Hakimjavadi⁴, Srikar Chamala⁴, Ranjala Ratnayake^{2

3}, Raad Z Gharaibeh^{6

7}, Chenglong Li^{2

3}, Hendrik Luesch^{2

3}, Thomas D Schmittgen⁸

Affiliations

¹ Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
² Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.
³ Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, FL, USA.
⁴ Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
⁵ Department of Surgery, University of Arkansas for Medical Sciences, University of Florida, Gainesville, FL, USA.
⁶ Department of Medicine, University of Florida, Gainesville, FL, USA.
⁷ Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
⁸ Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. tschmittgen@ufl.edu.

^# Contributed equally.

Abstract

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 p48^Cre/+ and p48^Cre/+LSL-Kras^G12D/+ (KC) mice. LLL12B and TSA inhibited ADM in both KC and p48^Cre/+ mouse pancreatic organoids. Furthermore, treatment with LLL12B or TSA on dedifferentiated acini from p48^Cre/+ and KC mice that had undergone ADM produced morphologic and gene expression changes that suggest a reversal of ADM. Validation experiments using qRT-PCR (p48^Cre/+ 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.

Abstract

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