Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Schlesinger, Yehuda; Yosefov-Levi, Oshri; Kolodkin-Gal, Dror; Granit, Roy Z.; Peters, Luriano; Kalifa, Rachel; Xia, Liangyu; Nasereddin, Abedelmajeed; Shiff, Idit; Amran, Osher; Nevo, Yuval; Elgavish, Sharona; Atlan, Karine; Zamir, Gideon; Parnas, Oren

doi:10.1038/s41467-020-18207-z

Cited by 149 publications

(183 citation statements)

References 85 publications

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“…We used co-immunofluorescence (Co-IF) for EYFP and cell type markers in normal and injured CERTY pancreata to confirm marker expression and to validate transcriptomically-identified populations. In uninjured, tamoxifen-treated CERTY pancreata, EYFP expression is restricted to acinar cells (amylase+) and is absent from ductal (pan-cytokeratin) and islet cells (CHGA+), consistent with prior reports (Figure 2A-B) 13,16 . Under conditions of chronic injury, however, EYFP is expressed in both acinar and ductal cells (including tuft cells) as well as a large population of CHGA+ cells consistent with EEC formation (Figure 2A-B).…”

Section: Lineage Tracing and Scrna-seq Identifies Epithelial Heterogesupporting

confidence: 90%

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Lytle

Chen

et al. 2021

Preprint

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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 genetically wild type ADM, the associated transcriptional changes, and to identify markers of disease progression. METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate upon injury. Transcripts of over 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Single-cell trajectories were generated. Data were compared to gastric metaplasia and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population (Muc6+, Tff2+) resembling gastric pyloric, gland-base cells. Lineage trajectories suggest that this pyloric metaplasia is an intermediate cell identity between acinar cells and the generation of metaplastic tuft and enteroendocrine cells (EECs). 3-D electron microscopy demonstrates that all identified lineages populate ADM lesions. EECs exhibit substantial heterogeneity, including emergence of enterochromaffin (5-HT+) and delta (SST+) cells. Human pancreatitis shows a similar pyloric metaplasia phenotype and a conserved transcriptional program. CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo pyloric metaplasia to mucinous progenitor-like populations, some of which can then seed disparate tuft cell and EEC lineages. EEC subtypes are diverse with the potential to direct disease progression. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases. Keywords: plasticity, pancreatitis, paligenosis, SPEM, Tuft cells, Enteroendocrine cells

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Section: Lineage Tracing and Scrna-seq Identifies Epithelial Heterogesupporting

confidence: 90%

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Lytle

Chen

et al. 2021

Preprint

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“…To investigate the molecular effects of hyperinsulinemia in the context of PDAC initiation in an unbiased and cell type-specific manner, we undertook scRNAseq. Only a few studies have successfully conducted scRNAseq in the pancreas to date for studying pancreatic cancer (41)(42)(43).…”

Section: Single-cell Transcriptomics Reveals Effects Of Hyperinsulinementioning

confidence: 99%

Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics

Zhang

Winter

Wang

et al. 2021

Preprint

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Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that a ~50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice could be achieved with reduced insulin production. However, only female mice remained normoglycemic and only the gene dosage of rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Here, we studied PanIN lesion development in both male and female Ptf1aCreER;KrasLSL-G12D mice lacking the rodent specific Ins1 gene, and possessing one or two alleles of the wild-type Ins2 gene to modulate insulin production. High-fat diet induced hyperinsulinemia was transiently and modestly reduced, without affecting glucose tolerance, in male and female mice with only one allele of Ins2. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell populations, which were highly represented in our analysis. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. These data suggest a role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.

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“…Consistent with previous work, 26 however, we found that senescence markers did not fully overlap at the individual cell level, with a somewhat different distribution of expression of Cdkn2a and Ptgs2 observed in the scRNA-Seq analysis, suggesting that the Cox2 + cells are a subset among several types of non-dividing cell states within lesions. 33 The Ptf1a-CreER model, in which oncogenic Kras is activated in acinar cells, provides rapid PanIN formation in the absence of external induction of inflammation. In this model, we found that pharmacologic inhibition of Cox2 through sulindac, a nonsteroid anti-inflammatory drug, dramatically inhibited PanIN growth, suggesting that the Cox2 + cells provide the major protumourigenic inflammatory drive, essential for disease development.…”

Section: Discussionmentioning

confidence: 99%

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

Kolodkin-Gal

Roitman

Ovadya

et al. 2021

Gut

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ObjectiveCellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development.DesignTo uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment.ResultsWe found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma.ConclusionsThese findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

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Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Cited by 149 publications

References 85 publications

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

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