Zhibo Ma1, Nikki K Lytle1, Bob Chen2, Nidhi Jyotsana3, Sammy Weiser Novak4, Charles J Cho5, Leah Caplan3, Olivia Ben-Levy3, Abigail C Neininger3, Dylan T Burnette6, Vincent Q Trinh7, Marcus C B Tan8, Emilee A Patterson9, Rafael Arrojo E Drigo10, Rajshekhar R Giraddi1, Cynthia Ramos1, Anna L Means11, Ichiro Matsumoto12, Uri Manor4, Jason C Mills5, James R Goldenring13, Ken S Lau14, Geoffrey M Wahl1, Kathleen E DelGiorno15. 1. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California. 2. Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee. 3. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee. 4. Waitt Advanced Biophotonics Center, Salk Insitute for Biological Studies, La Jolla, California. 5. Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas. 6. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee. 7. Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. 8. Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee. 9. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee. 10. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee. 11. Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee. 12. Monell Chemical Senses Center, Philadelphia, Pennsylvania. 13. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee. 14. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee. 15. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: kathleen.delgiorno@vanderbilt.edu.
Abstract
BACKGROUND & AIMS: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression. METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype. CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.
BACKGROUND & AIMS: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression. METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype. CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.
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