Transcriptional Profile of Human Pancreatic Acinar Ductal Metaplasia

Jiang, Jinmai; Hakimjavadi, Hesamedin; Bray, J. W.; Perkins, Corey; Gosling, Alyssa; daSilva, Lais; Bulut, Gamze B.; Ali, Jamel; Setiawan, Veronica Wendy; Campbell‐Thompson, Martha; Chamala, Srikar; Schmittgen, Thomas D.

doi:10.1016/j.gastha.2023.02.003

Cited by 5 publications

(8 citation statements)

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“…It is noteworthy that in the KC mouse model, the top inhibited upstream regulator detected during ADM reversal (angiotensinogen, AGT) is the main precursor of angiotensin and part of the renin-angiotensin-aldosterone system ( Figure 13 ). These data corroborate our findings of angiotensinogen as the most upregulated pathway during both human and mouse ADM ( Jiang et al, 2023 ). Major components of the renin-angiotensin-aldosterone system (angiotensinogen and angiotensin receptors 1 and 2) were upregulated in rat pancreatic acinar cells during pancreatitis and treatment with the angiotensin receptor antagonist losartan inhibited the acinar digestion enzyme secretion ( Huang et al, 2016 ).…”

Section: Discussionsupporting

confidence: 92%

“…We annotated two sets of genes previously associated with acinar/ductal phenotype of pancreas or genes associated with onset or progression of PDAC, from the literature ( Benitz et al, 2019 ; Qadir et al, 2020 ). Volcano plots were constructed from the changes in expression of 27 acinar and 23 ductal/PDAC genes following ADM reversal as previously described ( Jiang et al, 2023 ). A list of the acinar and ductal/PDAC genes may be found in Supplementary Table S1 ( Benitz et al, 2019 ; Qadir et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

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Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

Atanasova,

Perkins,

Ratnayake

et al. 2024

Front. Pharmacol.

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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 p48Cre/+ (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 p48Cre/+; LSL-KrasG12D/+ (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.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

Atanasova,

Perkins,

Ratnayake

et al. 2024

Front. Pharmacol.

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“…We annotated 2 sets of genes previously associated with acinar/ductal phenotype of pancreas or genes associated with onset or progression of PDAC, from the literature [39; 40]. Volcano plots were constructed from the changes in expression of 27 acinar and 23 ductal/PDAC genes following ADM reversal as previously described [41]. A list of the acinar and ductal/PDAC genes may be found in Table S1 [39; 40].…”

Section: Methodsmentioning

confidence: 99%

Epigenetic Small-Molecule Screen for Inhibition and Reversal of Acinar Ductal Metaplasia in Mouse Pancreatic Organoids

Atanasova,

Perkins,

Ratnayake

et al. 2023

Preprint

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BackgroundAcinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development.MethodsWe developed a novel morphology-based screen using organoids from wildtype and p48Cre/+(Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA).ResultsOf 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 p48Cre/+;LSL-KrasG12D/+(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.ConclusionOur findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.

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“…Several publications emerged from this study that are published. [14][15][16][17][18] Pilot Project 2…”

Section: Projectmentioning

confidence: 99%

Florida-California Cancer Research, Education and Engagement (CaRE²) Health Equity Center: Structure, Innovations, and Initial Outcomes

Reams,

Odedina,

Carpten

et al. 2023

Cancer Control

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Introduction The Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE2 triad partnership. Methods CaRE2 serves diverse populations in Florida and California using a “molecule to the community and back” model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. Results Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE2-related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. Conclusion The CaRE2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

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Transcriptional Profile of Human Pancreatic Acinar Ductal Metaplasia

Cited by 5 publications

References 56 publications

Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

Epigenetic Small-Molecule Screen for Inhibition and Reversal of Acinar Ductal Metaplasia in Mouse Pancreatic Organoids

Florida-California Cancer Research, Education and Engagement (CaRE²) Health Equity Center: Structure, Innovations, and Initial Outcomes

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Transcriptional Profile of Human Pancreatic Acinar Ductal Metaplasia

Cited by 5 publications

References 56 publications

Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids

Epigenetic Small-Molecule Screen for Inhibition and Reversal of Acinar Ductal Metaplasia in Mouse Pancreatic Organoids

Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center: Structure, Innovations, and Initial Outcomes

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Florida-California Cancer Research, Education and Engagement (CaRE²) Health Equity Center: Structure, Innovations, and Initial Outcomes