Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury

Ma, Zhibo; Lytle, Nikki K.; Chen, Bob; Jyotsana, Nidhi; Novak, Sammy Weiser; Cho, Charles J.; Caplan, Leah; Ben-Levy, Olivia; Neininger, Abigail C.; Burnette, Dylan T.; Trinh, Vincent Quoc‐Huy; Tan, Marcus; Patterson, Emilee A.; Drigo, Rafael Arrojo e; Giraddi, Rajshekhar R.; Ramos, Cynthia; Means, Anna L.; Matsumoto, Ichiro; Manor, Uri; Mills, Jason C.; Goldenring, James R.; Lau, Ken S.; Wahl, Geoffrey M.; DelGiorno, Kathleen E.

doi:10.1053/j.gastro.2021.10.027

Cited by 52 publications

(101 citation statements)

References 75 publications

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“…Recently, we reported the formation of multiple EEC subtypes arising in injury-induced ADM ( Ma et al, 2021 ). These EECs include archetypal islet cell types (gamma and delta cells expressing pancreatic polypeptide (PP) and somatostatin (SST), respectively), as well as EECs found in the epithelial lining of the stomach and intestines (delta cells, enterochromaffin cells expressing (5-HT), and epsilon cells expressing ghrelin (GHRL)) ( Andersson-Rolf et al, 2000 ).…”

Section: Resultsmentioning

confidence: 99%

“…We have recently shown that EECs arise in the injured pancreas during ADM ( Ma et al, 2021 ). To determine when EEC formation occurs in pancreatic tumorigenesis, we conducted IHC on pancreas tissue from 6 or 12-month old Kras G12D ;Ptf1a Cre/+ ( KC ) mice and Kras G12D ;Trp53 R172H ;Pdx1-Cre ( KPC ) mice with or without PDAC for pan-EEC marker SYP.…”

Section: Resultsmentioning

confidence: 99%

“…Acinar-to-ductal metaplasia (ADM) is a reparative program in which pancreatic acinar cells transdifferentiate into ductal cells in response to injury or oncogenic mutation ( Giroux and Rustgi, 2017 ). Recently, we combined acinar cell lineage tracing in murine models and single cell RNA sequencing (scRNA-seq) and revealed that ADM does not result in the formation of homogeneous ductal cells but seeds a heterogeneous population that includes tuft cells and enteroendocrine cell (EEC) subtypes, identified by hormone expression ( DelGiorno et al, 2020a ; Ma et al, 2021 ). These ADM-derived EEC subtypes include gamma cells (pancreatic polypeptide, PP), delta cells (somatostatin, SST), epsilon cells (ghrelin, GHRL), and enterochromaffin cells (serotonin, 5-HT) ( Ma et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we combined acinar cell lineage tracing in murine models and single cell RNA sequencing (scRNA-seq) and revealed that ADM does not result in the formation of homogeneous ductal cells but seeds a heterogeneous population that includes tuft cells and enteroendocrine cell (EEC) subtypes, identified by hormone expression ( DelGiorno et al, 2020a ; Ma et al, 2021 ). These ADM-derived EEC subtypes include gamma cells (pancreatic polypeptide, PP), delta cells (somatostatin, SST), epsilon cells (ghrelin, GHRL), and enterochromaffin cells (serotonin, 5-HT) ( Ma et al, 2021 ). While these hormones are present in murine islet development and in normal human islets (to varying degrees), we define ADM populations as EECs due to incorporation into ducts and their similarity to analogous populations throughout the gut ( Wierup et al, 2002 ; Ohta et al, 2011 ; Ma et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…These ADM-derived EEC subtypes include gamma cells (pancreatic polypeptide, PP), delta cells (somatostatin, SST), epsilon cells (ghrelin, GHRL), and enterochromaffin cells (serotonin, 5-HT) ( Ma et al, 2021 ). While these hormones are present in murine islet development and in normal human islets (to varying degrees), we define ADM populations as EECs due to incorporation into ducts and their similarity to analogous populations throughout the gut ( Wierup et al, 2002 ; Ohta et al, 2011 ; Ma et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of only 11%, due, in part, to late diagnosis, making the need to understand early events in tumorigenesis critical. Acinar-to-ductal metaplasia (ADM), when not resolved, is a PDAC precursor. Recently, we showed that ADM is constituted by a heterogenous population of cells, including hormone-producing enteroendocrine cells (EECs: gamma, delta, epsilon, and enterochromaffin cells). In this study, we employed histopathological techniques to identify and quantify the abundance of EEC subtypes throughout pancreatic tumorigenesis in mouse models and human disease. We found that EECs are most abundant in ADM and significantly decrease with lesion progression. Co-immunofluorescence identifies distinct lineages and bihormonal populations. Evaluation of EEC abundance in mice lacking Pou2f3 demonstrates that the tuft cell master regulator transcription factor is not required for EEC formation. We compared these data to human neoplasia and PDAC and observed similar trends. Lastly, we confirm that EECs are a normal cellular compartment within the murine and human pancreatic ductal trees. Altogether, these data identify EECs as a cellular compartment of the normal pancreas, which expands early in tumorigenesis and is largely lost with disease progression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

et al. 2022

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Intrapancreatic fat, pancreatitis, and pancreatic cancer

Lilly

Astsaturov

Golemis

2023

Cell. Mol. Life Sci.

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Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-β, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.

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Improving the prognosis of pancreatic cancer: insights from epidemiology, genomic alterations, and therapeutic challenges

Jiang,

Zheng,

et al. 2023

Front. Med.

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Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury

Cited by 52 publications

References 75 publications

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

Intrapancreatic fat, pancreatitis, and pancreatic cancer

Improving the prognosis of pancreatic cancer: insights from epidemiology, genomic alterations, and therapeutic challenges

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